Ortho-anthranilamide derivatives as anti-coagulants

ABSTRACT

This invention is directed to compounds of formula (III): ##STR1## wherein B, C, D, E, R 1 , R 2  and R 3  are disclosed herein. These compounds are disclosed as being useful as anti-coagulants.

This application is a continuation-in-part application of U.S. patentapplication, Ser. No. 08/994,284, filed Dec. 19, 1997, now abandoned,which is incorporated by reference in full herein.

FIELD OF THE INVENTION

The present invention is directed to ortho-anthranilamide derivativesand their pharmaceutically acceptable salts, which inhibit the enzyme,factor Xa, thereby being useful as anti-coagulants. It also relates topharmaceutical compositions containing the derivatives or theirpharmaceutically acceptable salts, and methods of their use.

BACKGROUND OF THE INVENTION

Factor Xa is a member of the trypsin-like serine protease class ofenzymes. A one-to-one binding of factors Xa and Va with calcium ions andphospholipid forms the prothrombinase complex which converts prothrombinto thrombin. Thrombin, in turn, converts fibrinogen to fibrin whichpolymerizes to form insoluble fibrin.

In the coagulation cascade, the prothrombinase complex is the convergentpoint of the intrinsic (surface activated) and extrinsic (vesselinjury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363;and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulationcascade has been refined further with the discovery of the mode ofaction of tissue factor pathway inhibitor (TFPI) (Seminars in Hematology(1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serineprotease inhibitor with three Kunitz-type domains which competes withfactor Va for free factor Xa. Once formed, the binary complex of factorXa and TFPI becomes a potent inhibitor of the factor VIIa and tissuefactor complex.

Factor Xa can be activated by two distinct complexes, by tissuefactor-VIIa complex on the "Xa burst" pathway and by the factorIXa-VIIIa complex (TENase) of the "sustained Xa" pathway in thecoagulation cascade. After vessel injury, the "Xa burst" pathway isactivated via tissue factor (TF). Up regulation of the coagulationcascade occurs via increased factor Xa production via the "sustained Xa"pathway. Down regulation of the coagulation cascade occurs with theformation of the factor Xa-TFPI complex, which not only removes factorXa but also inhibits further factor formation via the "Xa burst"pathway. Therefore, the coagulation cascade is naturally regulated byfactor Xa.

The primary advantage of inhibiting factor Xa over thrombin in order toprevent coagulation is the focal role of factor Xa versus the multiplefunctions of thrombih. Thrombin not only catalyzes the conversion offibrinogen to fibrin, factor VIII to VIIIA, factor V to Va, and factorXI to XIa, but also activates platelets, is a monocyte chemotacticfactor, and mitogen for lymphocytes and smooth muscle cells. Thrombinactivates protein C, the in vivo anti-coagulant inactivator of factorsVa and VIIIa, when bound to thrombomodulin. In circulation, thrombin israpidly inactivated by antithrombin III (ATIII) and heparin cofactor II(HCII) in a reaction which is catalyzed by heparin or otherproteoglycan-associated glycosaminoglycans, whereas thrombin in tissuesis inactivated by the protease, nexin. Thrombin carries out its multiplecellular activation functions through a unique "tethered ligand"thrombin receptor (Cell (1991), Vol. 64, p. 1057), which requires thesame anionic binding site and active site used in fibrinogen binding andcleavage and by thrombomodulin binding and protein C activation. Thus, adiverse group of in vivo molecular targets compete to bind thrombin andthe subsequent proteolytic events will have very different physiologicalconsequences depending upon which cell type and which receptor,modulator, substrate or inhibitor binds thrombin.

Published data with the proteins antistasin and tick anti-coagulantpeptide (TAP) demonstrate that factor Xa inhibitors are efficaciousanti-coagulants (Thrombosis and Haemostasis (1992), Vol. 67, pp.371-376; and Science (1990), Vol. 248, pp. 593-596).

The active site of factor Xa can be blocked by either a mechanism-basedor a tight binding inhibitor (a tight binding inhibitor differs from amechanism-based inhibitor by the lack of a covalent link between theenzyme and the inhibitor). Two types of mechanism-based inhibitors areknown, reversible and irreversible, which are distinguished by ease ofhydrolysis of the enzyme-inhibitor link (Thrombosis Res (1992), Vol. 67,pp. 221-231; and Trends Pharmacol. Sci. (1987), Vol. 8, pp. 303-307). Aseries of guanidino compounds are examples of tight-binding inhibitors(Thrombosis Res. (1980), Vol. 19, pp. 339-349).Arylsulfonyl-arginine-piperidine-carboxylic acid derivatives have alsobeen shown to be tight-binding inhibitors of thrombin (Biochem. (1984),Vol. 23, pp. 85-90), as well as a series of arylamidine-containingcompounds, including 3-amidinophenylaryl derivatives (Thrombosis Res.(1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones(Thrombosis Res. (1980), Vol. 17, pp. 545-548). However, these compoundsdemonstrate poor selectivity for factor Xa.

Related Disclosures

European Published Patent Application 0 540 051 (Nagahara et al.)describes aromatic amidine derivatives. These derivatives are stated tobe capable of showing a strong anticoagulant effect through reversibleinhibition of factor Xa.

The synthesis of α,α'-bis(amidinobenzylidene)cycloalkanones andα,α'-bis(amidino-benzyl)cycloalkanones is described in Pharmazie (1977),Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as beingserine protease inhibitors.

U.S. Pat. No. 5,612,363 (Mohan et al.) describes N,N-di(aryl) cyclicurea derivatives. These compounds are stated to be factor Xa inhibitors,thereby being useful as anticoagulants.

U.S. Pat. No. 5,633,381 (Dallas et al.) describes (Z,Z), (Z,E) and (E,Z)isomers of substituted bis(phenylmethylene)cycloketones. These compoundsare disclosed as being factor Xa inhibitors, thereby being useful asanticoagulants.

U.S. Pat. No. 5,691,364 (Buckman et al.) describes benzamidinederivatives. These compounds are stated to be factor Xa inhibitors,thereby being useful as anticoagulants.

PCT Published Patent Application WO/97/21437 (Arnaiz et al.) describesnaphthyl-substituted benzimidazole derivatives. These compounds aredisclosed as being factor Xa inhibitors, thereby being useful asanticoagulants.

PCT Published Patent Application WO/97/29067 (Kochanny et al.) describesbenzamidine derivatives that are substituted by amino acid and hydroxyacid derivatives. These compounds are stated to be factor Xa inhibitors,thereby being useful as anticoagulants.

PCT Published Patent Applications WO/96/10022 (Faull et al.), WO97/29104(Faull et al.), and WO/97/28129 describe aminoheterocyclic compoundswhich are disclosed as being factor Xa inhibitors, thereby being usefulas anfithrombotics and anticoagulants.

The above references, published patent applications and U.S. patents areherein incorporated in full by reference.

SUMMARY OF THE INVENTION

This invention is directed to compounds or their pharmaceuticallyacceptable salts which inhibit human factor Xa and are therefore usefulas pharmacological agents for the treatment of disease-statescharacterized by thrombotic activity, i.e., as anti-coagulants.

Accordingly, in one aspect, this invention provides compounds of formula(III): ##STR2## wherein

m is 1 to 3;

n is 1 to 5; ##STR3##

is an aryl or a heterocyclic ring substituted by R² and one or more R¹groups; ##STR4##

is an aryl or a heterocyclic ring substituted by one or more R⁴ groups;

D and E are independently a linker selected from the group consisting of--N(R⁵)--C(X)--; --R⁸ --N(R⁵)--C(X)--; --N(R⁵)--C(X)--R⁸ --; --R⁸--N(R⁵)--C(X)--R⁸ --; --N(R⁵)--S(O)_(p) --; --R⁸ --N(R⁵)--S(O)_(p) --;--N(R⁵)--S(O)_(p) --R⁸ --; and --R⁸ --N(R⁵)--S(O)_(p) --R⁸ -- (where pis 0 to 2; X is oxygen, sulfur or H₂) where D and E can be attached tothe B ring having the R¹ and R² substituents by either terminus of theselected linker;

each R¹ is independently hydrogen, alkyl, aryl, aralkyl, halo,haloalkyl, cyano, --OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵,--C(O)N(R⁵)R⁶, --N(R⁵)R⁶, --O--C(O)R⁵, --N(R⁵)--CH(R¹²)--C(O)OR⁵,heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶) orheterocyclylalkyl (optionally substituted by alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶);

R² is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, --OR⁵,--S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵, --C(O)N(R⁵)R⁶,--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸ --N(R¹⁰)R¹¹,--C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--S(O)_(p) --R⁹ (where p is 0to 2), --C(R⁷)H--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --O--R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --C(R⁷)H--N(R⁵)R⁶, --C(R⁷)H--R⁸--N(R⁵)R⁶, --O--R⁸ --CH(OH)--CH₂ --N(R¹⁰)R¹¹, --O--R⁸ --N(R¹⁰)R¹¹,--O--R⁸ --O--C(O)R⁵, --O--R⁸ --CH(OH)--CH₂ --OR⁵, --O--(R⁸ --O)_(t) --R⁵(where t is 1 to 6), --O--(R⁸ --O)_(t) --R¹⁹ (where t is 1 to 6),--O--R⁸ --C(O)R⁵, --O--R⁸ --C(O)R¹⁹, --O--R⁸ --C(O)OR⁵, --N(R⁵)--R⁸--N(R¹⁰)R¹¹, --S(O)_(p) --R⁸ --N(R⁵)R⁶ (where p is 0 to 2), --S(O)_(p)--R⁸ --C(O)OR⁵ (where p is 0 to 2), or --N(R⁵)--CH(R¹²)--C(O)OR⁵ ;

R³ is aryl or heterocyclyl both substituted by one or more R¹⁴substituents independently selected from the group consisting ofhydrogen, alkyl, halo, formyl, acetyl, cyano, --R⁸ --CN, --N(R¹⁰)R¹¹,--R⁸ --N(R¹⁰)R¹¹, --R--N.sup.⊕ (R⁹)(R¹⁶)₂, --C(O)OR⁵, --R⁸ --C(O)OR⁵,--OR⁵, --R⁸ --OR⁵, --C(R⁷)H--O--R¹⁵, --S(O)_(p) --R¹⁵ (where p is 0 to2), --R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2), --S(O)_(p) --N(R⁵)R⁶(where p is 0 to 2), --C(O)N(R⁵)R⁶, --R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--(R⁸--O)_(t) --R⁵ (where t is 1 to 6), --R⁸ --N(R⁵)--(R⁸ --O)_(t) --R⁵(where t is 1 to 6), --R⁸ --O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--O--R⁸ --CH(OH)--CH₂ --OR⁵, --C(R⁷)H--O--R⁸ --CH(OH)--CH₂ --OR⁵,--C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t) --CH₂ --OR⁵ (where t is 1 to 6),--C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰,--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--O--N(R⁵)R⁶,heterocyclyl (wherein the heterocyclyl radical is not attached to therest of the molecule through a nitrogen atom and is optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), and heterocyclylalkyl (whereinthe heterocyclyl radical is not attached to the alkyl radical through anitrogen ring and is optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R--)R⁶ and --C(O)N(R⁵)R⁶);

each R⁴ is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro,--OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, or --R⁸ --N(R⁵)R⁶ ;

each R⁵ and R⁶ is independently hydrogen, alkyl, aryl or aralkyl;

each R⁷ is independently hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁰ and R¹¹ is independently hydrogen, alkyl, haloalkyl, aryl,aralkyl, formyl, cyano, --R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2),--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸--C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸--N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, --R⁸--N(R⁵)--P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶);

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, halo,haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸ --CN, ═N(R¹⁷), --OR⁵,--C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶,--R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is Ito 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR--⁵, --N(R--⁵)R⁶, and --C(O)N(R--⁵)R⁶);

R¹² is a side chain of an α-amino acid;

each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R--OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,heterocyclyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶),or heterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶);

or R⁵ and R¹⁵ together with the nitrogen to which they are attached forma N-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl;

each R¹⁶ is independently alkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁵--N(R⁵)R⁶, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); or

both R¹⁶ 's together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶,--C(O)R⁶, --C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸--O)_(t) --R⁵ (where t is 1 to 6);

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶ ;

R¹⁸ is hydrogen, alkyl, aryl, aralkyl, cyano, --C(O)OR⁵, or --NO₂ ; and

each R¹⁹ is cycloalkyl, haloalkyl, --R⁸ --OR⁵, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, --R⁸ --C(O)N(R⁵)R⁶, heterocyclyl (optionally substituted byalkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and--C(O)N(R⁵)R⁶);

as a single stereoisomer or a mixture thereof; or a pharmaceuticallyacceptable salt thereof.

In another aspect, this invention provides compounds of formula (I):##STR5##

A is ═CH-- or ═N--;

m is 1 to 3;

n is 1 to 4;

D is --N(R⁵)--C(Z)-- or --N(R⁵)--S(O)_(p) -- (where p is 0 to 2; Z isoxygen, sulfur or H₂ ; and the nitrogen atom is directly bonded to thephenyl ring having the R¹ and R² substituents);

E is --C(Z)--N(R⁵)-- or --S(O)_(p) --N(R )-- (where p is 0 to 2; Z isoxygen, sulfur or H₂ ; and the nitrogen atom can be bonded to the phenylring having the R¹ and the R² substituents or to the aromatic ringhaving the R⁴ substituent);

each R¹ is independently hydrogen, alkyl, aryl, aralkyl, halo,haloalkyl, cyano, --OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵,--C(O)N(R⁵)R⁶, --N(R⁵)R⁶, --O--C(O)R⁵, or --N(R⁵)--CH(R¹²)--C(O)OR⁵ ;

or two adjacent R¹ 's together with the carbons to which they areattached form a heterocyclic ring fused to the phenyl ring wherein theheterocyclic ring is optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl and aralkyl;

R² is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, --OR⁵,--(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵, --OC(O)--R⁵,--C(O)N(R⁵)R⁶, --N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸--N(R¹⁰)R¹¹, --C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--S(O)_(p) --R⁹(where p is 0 to 2), --C(R⁷)H--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--O--R⁸ --S(O)O_(p) --R⁹ (where p is 0 to 2), --C(R⁷)H--N(R⁵)R⁶,--C(R⁷)H--R⁸ --N(R⁵)R⁶, --O--R⁸ --CH(OH)--CH₂ --N(R¹⁰)R¹¹, --O--R⁸--N(R¹⁰)R¹¹, --O--R⁸ --O--C(O)R⁵, --O--R⁸ --CH(OH)--CH₂ --OR⁵, --O--(R⁸--O)_(t) --R⁵ (where t is 1 to 6), --O--(R⁸ --O)_(t) --R¹⁹ (where t is 1to 6), --O--R⁸ --C(O)R⁵, --O--R⁸ --C(O)R¹⁹, --O--R⁸ --C(O)OR⁵,--N(R⁵)--R⁸ --N(R¹⁰)R¹¹, --S(O)_(p) R⁸ --N(R⁵)R⁶ (where p is 0 to 2),--S(O)_(p) --R⁸ --C(O)OR⁵ (where p is 0 to 2), or--N(R⁵)--CH(R¹²)--C(O)OR⁵ ;

R³ is a radical of formula (i): ##STR6## where:

r is 1 or 2;

R¹³ is hydrogen, alkyl, halo, haloalkyl, --N(R⁵)R⁶, --C(R⁷)H--N(R⁵)⁶,--OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R⁸ --N(R⁵)R⁶ (where p is 0 to 2) orheterocyclylalky (where the heterocyclic ring is optionally substitutedby one or more substituents selected from the group consisting of alkyl,halo, aralkyl, nitro and cyano); and

each R¹⁴ is independently hydrogen, alkyl, halo, formyl, acetyl, cyano,--R⁸ --CN, --N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸ N(R¹⁰)R¹¹,--C(R⁷)H--N.sup.⊕ (R⁹)(R¹⁶)₂, --C(R⁷)H--R⁸ --N.sup.⊕ (R⁹)(R¹⁶ )₂,--C(O)OR⁵, --C(R⁷)H--C(O)OR⁵, --C(R⁷)H--R⁸ --C(O)OR⁵, --OR⁵,--C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--O--R¹⁵, --S(O)_(p) R¹⁵(where p is 0 to 2), --C(R⁷)H--S(O)_(p) --R¹⁵ (where p is 0 to 2),--C(R⁷)H--R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2), --S(O)_(p) --N(R⁵)R⁶(where p is 0 to 2), --C(O)N(R⁵)R⁶, --C(R⁷)H--C(O)N(R⁵)R⁶, --C(R⁷)H--R⁸--C(O)N(R⁵)R⁶, --C(R⁷)H--N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--R⁸ --N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --C(R⁷)H--R⁸--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --O--R⁸ --CH(OH)--CH₂ --OR⁵,--C(R⁷)H--O--R⁸ --CH(OH)--CH₂ --OR⁵, --C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t)--CH₂ --OR⁵ (where t is 1 to 6), --C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰,--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--O--N(R⁵)R⁶,heterocyclyl (wherein the heterocyclyl radical is not attached to theradical of formula (i) through a nitrogen atom and is optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (whereinthe heterocyclyl radical is not attached to the alkyl radical through anitrogen atom and is optionally substituted by one or more substituentsselected from the group consisting of alky, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶);

or R³ is a radical of the formula (ii): ##STR7## where v is 1 to 4;

R¹³ is as defined above for formula (i); and

R¹⁴ is as defined above for formula (i);

each R⁴ is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro,--OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, or --R⁸ --N(R⁵)R⁶ ;

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁷ is independently hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, haloalkyl, aryl,aralkyl, formyl, cyano, --R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2),--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸--C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)═C(R¹⁸)R₁₀, --R⁸--N(R⁵)--P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶);

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, halo,haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸ --CN, ═N(R¹⁷), --OR⁵,--C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶,--R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1to 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶);

R¹² is a side chain of an α-amino acid;

each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶);

or R⁵ and R¹⁵ together with the nitrogen to which they are attached forma N-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl;

each R¹⁶ is independently alkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁸--N(R⁵)R⁶, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); or

both R¹⁶ 's together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)R⁵,--C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸ --O)_(t) --R⁵(where t is 1 to 6);

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶ ;

R¹⁸ is hydrogen, alkyl, aryl, aralkyl, cyano, --C(O)OR⁵, or --NO₂ ; and

each R¹⁹ is cycloalkyl, haloalkyl, --R⁸ --OR⁵, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, --R⁸ --C(O)N(R⁵)R⁶, heterocyclyl (optionally substituted byalkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and--C(O)N(R⁵)R⁶);

as a single stereoisomer or a mixture thereof; or a pharmaceuticallyacceptable salt thereof; provided that when A is ═CH--, m is 1, n is 1,D is --N(H)--C(O)-- (where the nitrogen atom is directly bonded to thephenyl ring having the R¹ and R² substituents), E is --C(O)--N(H)--(where the nitrogen atom is directly bonded to the phenyl ring havingthe R⁴ substitutent), R¹ is hydrogen and R² is in the 5-position and ismethyl, R⁴ is in the 4-position and is fluoro, R³ can not be a radicalof formula (ii) where v is 1, R¹⁴ is hydrogen, and R¹³ is chloro.

In another aspect, this invention provides compositions useful intreating a human having a disease-state characterized by thromboticactivity, which composition comprises a therapeutically effective amountof a compound of the invention as described above, without the proviso,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In another aspect, this invention provides a method of treating a humanhaving a disease-state characterized by thrombotic activity, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above, without the proviso.

In another aspect, this invention provides a method of treating a humanhaving a disease-state alleviated by the inhibition of factor Xa, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above, without the proviso.

In another aspect, this invention provides a method of inhibiting humanfactor Xa in vitro by the administration of a compound of the invention,without the proviso.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

"Alkyl" refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to six carbon atoms, and which is attachedto the rest of the molecule by a single bond, e.g., methyl, ethyl,n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like.

"Alkoxy" refers to a radical of the formula --OR_(a) where R_(a) is analkyl radical as defined above, e.g., methoxy, ethoxy, propoxy, and thelike.

"Alkoxyalkyl" refers to a radical of the formula --R_(a) --OR_(a) whereeach R_(a) is independently an alkyl radical as defined above, e.g.,2-methoxyethyl, methoxymethyl, 3-ethoxypropyl, and the like.

"Alkylene chain" refers to straight or branched chain divalent radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation and having from one to six carbon atoms, e.g., methylene,ethylene, propylene, n-butylene and the like.

"Alkylidene chain" refers to a straight or branched chain unsaturateddivalent radical consisting solely of carbon and hydrogen atoms, havingfrom two to six carbon atoms, wherein the unsaturation is present onlyas double bonds and wherein a double bond can exist between the firstcarbon of the chain and the rest of the molecule, e.g., ethylidene,propylidene, n-butylidene, and the like.

"Alkylidyne chain" refers to a straight or branched chain unsaturateddivalent radical consisting solely of carbon and hydrogen atoms havingfrom two to six carbon atoms, wherein the unsaturation is present onlyas triple bonds and wherein a triple bond can exist between the firstcarbon of the chain and the carbon atom of the rest of the molecule towhich it is attached, e.g., propylid-2-ynyl, n-butylid-1-ynyl, and thelike.

"Amino" refers to the --NH₂ radical.

"Aminocarbonyl" refers to the --C(O)NH₂ radical.

"Aryl" refers to a phenyl or naphthyl radical. Unless otherwiseindicated, the term "aryl" refers to phenyl or naphthyl radicals whichare optionally substituted by alkyl, halo, --OR⁵ (where R⁵ is hydrogen,alkyld aryl or aralkyl).

"Aralkyl" refers to a radical of the formula --R_(a) R_(b) where R_(a)is an alkyl radical, as defined above, substituted by R_(b), an arylradical, as defined above, e.g., benzyl.

"α-Amino Acids" refer to naturally occurring and commercially availableamino acids and optical isomers thereof. Typical natural andcommercially available amino acids are glycine, alanine, serine,homoserine, threonine, valine, norvaline, leucine, isoleucine,norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine,arginine, cysteine, homocysteine, methionine, phenylalanine,homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine,para-tyrosine, tryptophan, glutamine, asparagine, proline andhydroxyproline. A "side chain of an α-amino acid" refers to the radicalfound on the α-carbon of an α-amino acid as defined above, for example,hydrogen (for glycine), methyl (for alanine), benzyl (forphenylalanine), and the like.

"Cycloalkyl" refers to a 3- to 7-membered monocyclic cyclic radicalwhich is saturated, and which consists solely of carbon and hydrogenatoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and thelike.

"DMF" refers to N,N-dimethylformamide.

"DMSO" refers to dimethylsulfoxide.

"Dialkylamino" refers to a radical of the formula --N(R_(a))R_(a) whereeach R_(a) is independently an alkyl radical as defined above, e.g.,dimethylamino, diethylamino, (iso-propyl)(ethyl)amino, and the like.

"Dialkylaminocarbonyl" refers to a radical of the formula--C(O)N(R_(a))R_(a) where each R_(a) is independently an alkyl radicalas defined above, e.g., (dimethylamino)carbonyl, (diethylamino)carbonyl,((iso-propyl)(ethyl)amino)carbonyl, and the like.

"Halo" refers to bromo, chloro, iodo or fluoro.

"Haloalkyl" refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

"Heterocyclic ring" refers to a stable 3- to 15-membered ring radicalwhich consists of carbon atoms and from one to five heteroatoms selectedfrom the group consisting of nitrogen, phosphorus, oxygen and sulfur.For purposes of this invention, the heterocyclic ring radical may be amonocyclic, bicyclic or tricyclic ring system, which may include fusedor bridged ring systems, and the nitrogen, phosphorus, carbon or sulfuratoms in the heterocyclic ring radical may be optionally oxidized tovarious oxidation states. In addition, the nitrogen atom may beoptionally quaternized; and the ring radical may be partially or fullysaturated or aromatic. Examples of such heterocyclic ring radicalsinclude, but are not limited to, azetidinyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl,morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl,isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl,isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl,benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyland oxadiazolyl. For those compounds where two adjacent R¹ 's togetherwith the carbons to which they are attached form a heterocyclic ringfused to the phenyl ring, the most preferred heterocyclic ring is thedioxolane ring (with the phenyl ring forms a benzodioxole ring).

"Heterocyclyl" refers to a heterocyclic ring radical as defined above,except that the heterocyclyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

"Heterocyclylalkyl" refers to a radical of the formula --R_(a) --R_(c)where R_(a) is an alkyl radical as defined above and R_(c) is aheterocyclyl ring radical as defined above, for example,(4-methylpiperazin-1-yl)methyl, (morpholin-4-yl)methyl,2-(oxazolin-2-yl)ethyl, and the like.

"N-heterocyclic ring" refers to those heterocyclic ring radicals definedabove which contain at least one nitrogen. The N-heterocyclic ringradical is attached to the main structure through a nitrogen atom in thering. Examples include, but are not limited to, 4--methylpiperazin-1-yl,pyrrolidin-1-yl, morpholin-4-yl, oxazolin-2-yl, and the like. TheN-heterocyclic ring may contain up to three additional hetero atoms.Examples include tetrazolyl, triazolyl, thiomorpholinyl, oxazinyl, andthe like.

"HPLC" refers to high pressure liquid chromatography.

"Monoalkylamino" refers to a radical of the formula --N(H)R_(a) whereR_(a) is an alkyl radical as defined above, e.g., methylamino,ethylamino, (t-butyl)amino, and the like.

"Monoalkylaminocarbonyl" refers to a radical of the formula--C(O)N(H)R_(a) where R_(a) is an alkyl radical as defined above, e.g.,(methylamino)carbonyl, (ethylamino)carbonyl, ((t-butyl)amino)carbonyl,and the like.

"Optional" or "optionally" means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, "optionally substituted aryl" means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

"Pharmaceutically acceptable salt" includes both acid and base additionsalts.

"Pharmaceutically acceptable acid addition salt" refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, andorganic acids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

"Pharmaceutically acceptable base addition salt" refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

"Therapeutically effective amount" refers to that amount of a compoundof the invention which, when administered to a human in need thereof, issufficient to effect treatment, as defined below, for disease-statescharacterized by thrombotic activity. The amount of a compound of theinvention which constitutes a "therapeutically effective amount" willvary depending on the compound, the disease-state and its severity, andthe age of the human to be treated, but can be determined routinely byone of ordinary skill in the art having regard to his own knowledge andto this disclosure.

"THF" refers to tetrahydrofuran.

"Treating" or "treatment" as used herein covers the treatment of adisease-state in a human, which disease-state is characterized bythrombotic activity, and includes:

(i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it;

(ii) inhibiting the disease-state, ie., arresting its development; or

(iii) relieving the disease-state, ie., causing regression of thedisease-state.

The yield of each of the reactions described herein is expressed as apercentage of the theoretical yield.

For purposes of this invention, in the substituent "--R⁸ --OR⁵ ", the"--OR⁵ " group may be attached to any carbon in the alkylene, alkylideneor alkylidyne chain.

Some of the compounds of the invention may have imino, amino, oxo orhydroxy substituents off aromatic heterocyclic ring systems. Forpurposes of this disclosure, it is understood that such imino, amino,oxo or hydroxy substituents may exist in their corresponding tautomericform, i.e., amino, imino, hydroxy or oxo, respectively.

For purposes of this invention, unless otherwise indicated, the linkermoieties between the B ring and the C ring ("E") and between the B ringand the R³ moiety ("D") may be independently attached to the B ring oneither end of the linker.

For purposes of this invention, the quaternary salts represented by"--N.sup.⊕ (R⁹)(R¹⁶)₂ " include aromatic rings wherein both R¹⁶ 'stogether with the nitrogen to which they are attached form an aromaticring and it is understood that R⁹ is not present.

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms, oxidized sulfur atoms orquatemized nitrogen atoms in their structure. The compounds of theinvention and their pharmaceutically acceptable salts may thereforeexist as single stereoisomers, racemates, and as mixtures of enantiomersand diastereomers. The compounds may also exist as geometric isomers.All such single stereoisomers, racemates and mixtures thereof, andgeometric isomers are intended to be within the scope of this invention.Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art.

The nomenclature used herein is a modified form of the I.U.P.A.C. systemwherein the compounds of the invention are named as derivatives ofbenzamide. For example, a compound of the invention selected fromformula (I) where A is --N--; m is 1; n is 1; E is --C(O)--N(H)-- wherethe nitrogen atom is bonded to pyridine ring; D is --N(H)--C(O)-- wherethe nitrogen atom is bonded to the phenyl ring; R¹ is in the 5-positionand is chloro; R² is in the 3-position and is --N(R¹⁰)R¹¹ where R¹⁰ andR¹¹ together with nitrogen to which they are attached form amorpholin-4-yl ring; R⁴ is in the 5-position and is chloro; and R³ isselected from formula (i): ##STR8## where R¹³ is chloro,r is 1 and R¹⁴is --C(R⁷)H--N(R¹⁰)R¹¹ where R⁷ is hydrogen, R¹⁰ is methyl and R¹¹ is1-methylpiperidin-4-yl; i.e., a compound of the following formula (withposition numbers indicated): ##STR9## is named herein asN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide.

For purposes of this specification, parenthesis are used to denotesubstituents of a main atom. For example, --C(R⁷)H--N(R¹⁰)R¹¹ refers tothe radical: ##STR10##

Carbonyl and thiocarbonyl groups are indicated as --C(O)-- and --C(S)--,respectively, and optionally substituted imino radicals are indicated as═N(R¹⁷).

Substituents having repeating sections are indicated by brackets (orparenthesis) and the repeating integer. For example, the substituent--C(R⁷)H--R⁸ --(R⁸ --O)_(t) --R⁵ where t is 3 refers to the thesubstituent --C(R⁷)H--R⁸ --R⁸ --O--R⁸ --O--R⁸ --O--R⁵.

Utility and Administration

A. Utility

The compounds of the invention are inhibitors of the serine protease,factor Xa, and are therefore useful in disease-states characterized bythrombotic activity based on factor Xa's role in the coagulation cascade(see Background of the Invention above). Primarily, the compounds of theinvention are useful as anti-coagulants. A primary indication for thecompounds is prophylaxis for long term risk following myocardialinfarction. Additional indications are prophylaxis of deep veinthrombosis (DVT) following orthopedic surgery or prophylaxis of selectedpatients following a transient ischemic attack. The compounds of theinvention may also be useful for indications in which coumarin iscurrently used, such as for DVT or other types of surgical interventionsuch as coronary artery bypass graft and percutaneous transluminalcoronary angioplasty. The compounds are also useful for the treatment ofthrombotic complications associated with acute promyelocytic leukemia,diabetes, multiple myelomas, disseminated intravascular coagulationassociated with septic shock, purpura fulminanas associated infection,adult respiratory distress syndrome, unstable angina, and thromboticcomplications associated with aortic valve or vascular prosthesis. Thecompounds are also useful for prophylaxis for thrombotic diseases, inparticular in patients who have a high risk of developing such disease.

In addition, the compounds of the invention are useful as in vitrodiagnostic reagents for selectively inhibiting factor Xa withoutinhibiting other components of the coagulation cascade.

B. Testing

The primary bioassays used to demonstrate the inhibitory effect of thecompounds of the invention on factor Xa are simple chromogenic assaysinvolving only serine protease, the compound of the invention to betested, substrate and buffer (see, e.g., Thrombosis Res. (1979), Vol.16, pp. 245-254). For example, four tissue human serine proteases can beused in the primary bioassay, free factor Xa, prothrombinase, thrombin(IIa) and tissue plasminogen activator (tPA). The assay for tPA has beensuccessfully used before to demonstrate undesired side effects in theinhibition of the fibrinolytic process (see, e.g., J. Med. Chem. (1993),Vol. 36, pp. 314-319).

Another bioassay useful in demonstrating the utility of the compounds ofthe invention in inhibiting factor Xa demonstrates the potency of thecompounds against free factor Xa in citrated plasma. For example, theanticoagulant efficacy of the compounds of the invention will be testedusing either the prothrombin time (PT), or activated partialthromboplastin time (aPTT) while selectivity of the compounds is checkedwith the thrombin clotting time (TCT) assay. Correlation of the K_(i) inthe primary enzyme assay with the K_(i) for free factor Xa in citratedplasma will screen against compounds which interact with or areinactivated by other plasma components. Correlation of the K_(i) withthe extension of the PT is a necessary in vitro demonstration thatpotency in the free factor Xa inhibition assay translates into potencyin a clinical coagulation assay. In addition, extension of the PT incitrated plasma can be used to measure duration of action in subsequentpharmacodynamic studies.

For further information on assays to demonstrate the activity of thecompounds of the invention, see R. Lottenberg et al., Methods inEnzymology (1981), Vol. 80, pp. 341-361, and H. Ohno et al., ThrombosisResearch (1980), Vol. 19, pp. 579-588.

C. General Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally,topically, transdermally, or rectally, in the form of solid, semi-solid,lyophilized powder, or liquid dosage forms, such as for example,tablets, suppositories, pills, soft elastic and hard gelatin capsules,powders, solutions, suspensions, or aerosols, or the like, preferably inunit dosage forms suitable for simple administration of precise dosages.The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. Preferably, the composition will be about 5%to 75% by weight of a compound(s) of the invention, or apharmaceutically acceptable salt thereof, with the rest being suitablepharmaceutical excipients.

The preferred route of administration is oral, using a convenient dailydosage regimen which can be adjusted according to the degree of severityof the disease-state to be treated. For such oral administration, apharmaceutically acceptable composition containing a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, is formed bythe incorporation of any of the normally employed excipients, such as,for example, pharmaceutical grades of mannitol, lactose, starch,pregelatinized starch, magnesium stearate, sodium saccharin, talcum,cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propylgallate, and the like. Such compositions take the form of solutions,suspensions, tablets, pills, capsules, powders, sustained releaseformulations and the like.

Preferably such compositions will take the form of capsule, caplet ortablet and therefore will also contain a diluent such as lactose,sucrose, dicalcium phosphate, and the like; a disintegrant such ascroscarmellose sodium or derivatives thereof; a lubricant such asmagnesium stearate and the like; and a binder such as starch, gumacacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, andthe like.

The compounds of the invention, or their pharmaceutically acceptablesalts, may also be formulated into a suppository using, for example,about 0.5% to about 50% active ingredient disposed in a carrier thatslowly dissolves within the body, e.g., polyoxyethylene glycols andpolyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc., a compound(s) of the invention(about 0.5% to about 20%), or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike, to thereby form a solution or suspension.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state alleviated by the inhibition of factor Xa inaccordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed; the metabolic stability and length of actionof the compound; the age, body weight, general health, sex, and diet ofthe patient; the mode and time of administration; the rate of excretion;the drug combination; the severity of the particular disease-states; andthe host undergoing therapy. Generally, a therapeutically effectivedaily dose is from about 0.14 mg to about 14.3 mg/kg of body weight perday of a compound of the invention, or a pharmaceutically acceptablesalt thereof, preferably, from about 0.7 mg to about 10 mgfkg of bodyweight per day; and most preferably, from about 1.4 mg to about 7.2mg/kg of body weight per day. For example, for administration to a 70 kgperson, the dosage range would be from about 10 mg to about 1.0 gram perday of a compound of the invention, or a pharmaceutically acceptablesalt thereof, preferably from about 50 mg to about 700 mg per day, andmost preferably from about 100 mg to about 500 mg per day.

PREFERRED EMBODIMENTS

Of the compounds disclosed in the Summary of the Invention, certaincompounds are preferred.

The most preferred compounds of the invention are those compoundsselected from formula (III) having the formula (I): ##STR11##

A is ═CH-- or ═N--;

m is 1 to 3;

n is 1 to 4;

D is --N(R⁵)--C(Z)-- or --N(R⁵)--S(O)_(p) -- (where p is 0 to 2; Z isoxygen, sulfur or H₂ ; and the nitrogen atom is directly bonded to thephenyl ring having the R¹ and R² substituents);

E is --C(Z)--N(R⁵)-- or --S(O)_(p) --N(R⁵)-- (where p is 0 to 2; Z isoxygen, sulfur or H₂ ; and the nitrogen atom can be bonded to the phenylring having the R¹ and the R² substituents or to the aromatic ringhaving the R⁴ substituent);

each R¹ is independently hydrogen, alkyl, aryl, aralkyl, halo,haloalkyl, cyano, --OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵,--C(O)N(R⁵)R⁶, --N(R⁶)R⁶, --O--C(O)R⁵, or --N(R)--CH(R¹²)--C(O)OR⁵ ;

or two adjacent R¹ 's together with the carbons to which they areattached form a heterocyclic ring fused to the phenyl ring wherein theheterocyclic ring is optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl and aralkyl;

R² is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, --OR⁵,--S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵, --OC(O)--R⁵,--C(O)N(R⁵)R⁶, --N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸--N(R¹⁰)R¹¹, --C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--S(O)_(p) --R⁹(where p is 0 to 2), --C(R⁷)H--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--O--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --C(R⁷)H--N(R⁵)R⁶,--C(R⁷)H--R⁸ --N(R⁵)R⁶, --O--R⁸ --CH(OH)--CH₂ --N(R¹⁰)R¹¹, --O--R⁸--N(R¹⁰)R¹¹, --O--R⁸ --O--C(O)R⁵, --O--R⁸ --CH(OH)--CH₂ --OR⁵, --O--(R⁸--O)_(t) R⁵ (where t is 1 to 6), --O--(R⁸ --O)_(t) R¹⁹ (where t is 1 to6), --O--R⁸ --C(O)R⁵, --O--R⁸ --C(O)R¹⁹, --O--R⁸ --C(O)OR⁵, --N(R⁵)--R⁸--N(R¹⁰)R¹¹, --S(O)_(p) R⁸ --N(R⁵)R⁶ (where p is 0 to 2), --S(O)_(p)--R⁸ --C(O)OR⁵ (where p is 0 to 2), or --N(R⁵)--CH(R¹²)--C(O)OR⁵ ;

R³ is a radical of formula (i): ##STR12## where:

r is 1 or 2;

R¹³ is hydrogen, alkyl, halo, haloalkyl, --N(R⁵)R⁵, --C(R⁷)H--N(R⁵)R⁶,--OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R⁸ --N(R⁵)R⁶ (where p is 0 to 2) orheterocyclylalkyl (where the heterocyclic ring is optionally substitutedby one or more substituents selected from the group consisting of alkyl,halo, aralkyl, nitro and cyano); and

each R¹⁴ is independently hydrogen, alkyl, halo, formyl, acetyl, cyano,--R⁸ --CN, --N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸ --N(R¹⁰)R¹¹,--C(R⁷)H--N.sup.⊕ (R⁹)(R¹⁶)₂, --C(R⁷)H--R⁸ --N.sup.⊕ (R⁹)(R¹⁶)₂,--C(O)OR⁵, --C(R⁷)H--C(O)OR⁵, --C(R⁷)H--R⁸ --C(O)OR₅, --OR⁵,--C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--O--R¹⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --C(R⁷)H--S(O)_(p) --R¹⁵ (where p is 0 to 2),--C(R⁷)H--R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2), --S(O)_(p) --N(R⁵)R⁶(where p is 0 to 2), --C(O)N(R⁵)R⁶, --C(R⁷)H--C(O)N(R⁵)R⁶, --C(R⁷)H--R⁸--C(O)N(R⁵)R⁶, --C(R⁷)H--N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--R⁸ --N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --C(R⁷)H--R⁸--O--(R⁸ --O)_(t) -R⁵ (where t is 1 to 6), --O--R⁸ --CH(OH)--CH₂ --OR⁵,--C(R⁷)H--O--R⁸ --CH(OH)--CH₂ --OR⁵, --C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t)--CH₂ --OR⁵ (where t is 1 to 6), --C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰,--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--O--N(R⁵)R⁶,heterocyclyl (wherein the heterocyclyl radical is not attached to theradical of formula (i) through a nitrogen atom and is optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (whereinthe heterocyclyl radical is not attached to the alkyl radical through anitrogen atom and is optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶);

or R³ is a radical of the formula (ii): ##STR13## where v is 1 to 4;

R¹³ is as defined above for formula (i); and

R¹⁴ is as defined above for formula (i); and

each R⁴ is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro,--OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, or --R⁸ --N(R⁵)R⁶ ;

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁷ is independently hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, haloalkyl, aryl,aralkyl, formyl, cyano, --R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2),--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸--C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵, --C(O)--N(R⁵)R₁₅, --R⁸--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸--N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, --R⁸--N(R⁵)--P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶);

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, halo,haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸ --CN, ═N(R¹⁷), --OR⁵,--C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶,--R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1to 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁵);

R¹² is a side chain of an α-amino acid;

each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶);

or R⁵ and R¹⁵ together with the nitrogen to which they are attached forma N-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl;

each R¹⁶ is independently alkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁸--N(R⁵)R⁶, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); or

both R¹⁶ 's together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)R⁵,--C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸ --O)_(t) --R⁵(where t is 1 to 6);

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶ ;

R¹⁸ is hydrogen, alkyl, aryl, aralkyl, cyano, --C(O)OR⁵, or --NO₂ ; and

each R¹⁹ is cycloalkyl, haloalkyl, --R⁸ --OR⁵, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, --R⁸ --C(O)N(R⁵)R⁶, heterocyclyl (optionally substituted byalkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and--C(O)N(R⁵)R⁶).

Of these compounds, a preferred group of compounds are those compoundswherein:

A is ═N--;

m is 1 to 3;

n is 1 to 4;

D is --N(R⁵)--C(Z)-- (where Z is oxygen, sulfur or H₂, and R⁵ ishydrogen or alkyl);

E is --C(Z)--N(R⁵)-- (where Z is oxygen, sulfur or H₂, R⁵ is hydrogen oralkyl, and the nitrogen is attached to the pyridinyl ring);

R¹ is halo or haloalkyl;

R² is --N(R¹⁰)R¹¹, --O--R⁸ --S(O)_(p) --R⁹ (where p is 0), --O--R⁸--C(O)OR⁵, --O--(R⁸ --O)_(t) --R⁵ (where t is 1) or --O--R⁸ --N(R¹⁰)R¹¹where:

each R⁵ is independently hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene chain;

R⁹ is alkyl; and

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, or --R⁸ --O--R⁵(where R⁸ is a straight or branched alkylene chain and R⁵ is hydrogen oralkyl);

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to one additional heteroatoms, where the N-heterocyclic ring is optionally substituted by alkyl;

R³ is a radical of the formula (i): ##STR14##

where r is 1;

R¹³ is halo; and

R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where:

R⁷ is hydrogen; and

R¹⁰ and R¹¹ together with the nitrogen to which they are attached formpiperazinyl optionally substituted by one or more substituents selectedfrom the group consisting of alkyl and --C(O)R⁵ ; and

R⁴ is hydrogen or halo.

Of this group of compounds, a preferred subgroup of compounds are thosecompounds wherein:

m is 1;

n is 1;

D is --N(H)--C(O)--;

E is --C(O)--N(H)-- (where the nitrogen is bonded to the 2-position ofthe pyridinyl ring);

R¹ is halo in the 5-position;

R² is --N(R¹⁰)R¹¹, --O--R⁸ --S(O)_(p) --R⁹ (where p is 0), --O--R⁸--C(O)OR⁵, --O--(R⁸ --O)_(t) --R⁵ (where t is 1) or --O--R⁸ --N(R¹⁰)R¹¹where:

each R⁵ is independently hydrogen, methyl or ethyl;

each R⁸ is independently a methylene, ethylene or propylene chain;

R⁹ is methyl or ethyl; and

R¹⁰ and R¹¹ are each independently hydrogen, methyl, ethyl, or --R⁸--O--R⁵ (where R⁸ is ethylene and R⁵ is hydrogen, methyl or ethyl); or

R¹⁰ and R¹¹ together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to one additional hetero atoms,where the N-heterocyclic ring is optionally substituted by alkyl;

R³ is a radical of the formula (i): ##STR15##

where r is 1;

R¹³ is chloro; and

R is in the 4-position and is --C(R⁷)H--N(R¹⁰)R¹¹ where:

R⁷ is hydrogen; and

R¹⁰ and R¹¹ together with the nitrogen to which they are attached formpiperazinyl optionally substituted by methyl or ethyl; and

R⁴ is hydrogen, bromo or chloro in the 5-position.

Of this subgroup of compounds, a preferred class of compounds are thosecompounds wherein:

R¹ is chloro;

R² is --O--R⁸ --S(O)_(p) --R⁹ (where p is 0), --O--R⁸ --C(O)OR⁵ or--O--(R⁸ --O)_(t) --R⁵ (where t is 1 or 2) where:

each R⁵ is independently hydrogen, methyl or ethyl;

each R⁸ is independently a methylene, ethylene or propylene chain; and

R⁹ is methyl or ethyl.

Of this class of compounds, more preferred compounds are those compoundsselected from the group consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(methylthio)methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-ethoxyethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,and

N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide.

Of this subgroup of compounds, another preferred class of compounds arethose compounds wherein:

R¹ is chloro; and

R² is --N(R¹⁰)R¹¹ or --O--R⁸ --N(R¹⁰)R¹¹ where:

R⁸ is a methylene, ethylene or propylene chain; and

R¹⁰ and R¹¹ are each independently hydrogen, methyl, ethyl, or --R⁸--O--R⁵ (where R⁸ is ethylene and R⁵ is hydrogen, methyl or ethyl).

Of this class of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(N'-methyl-N'-(2-hydroxyethyl)amino)propoxy)-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-amino-5-chlorobenzamide.

Of this subgroup of compounds, another preferred class of compounds arethose compounds wherein:

R¹ is chloro;

R² is --N(R¹⁰)R¹¹ or --O--R⁸ --N(R¹⁰)R¹¹ where:

R⁸ is methylene, ethylene or propylene; and

R¹⁰ and R¹¹ together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to one additional hetero atoms,where the N-heterocyclic ring is optionally substituted by alkyl and isselected from the group consisting of morpholinyl, piperazinyl,pyrrolidinyl or imidazolyl.

Of this class of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-morpholinylpropoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolidin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(imidazol-1-yl)propoxy)-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)aminol-3-(morpholin4-yl)-5-chlorobenzamide.

Of the compounds of formula (I) described above, another preferred groupof compounds are those compounds of formula (I) wherein:

A is ═N--;

m is 1 to 3;

n is 1 to 4;

D is --N(R⁵)--C(Z)-- (where Z is oxygen, sulfur or H₂, and R⁵ ishydrogen or alkyl);

E is --C(Z)--N(R⁵)-- (where Z is oxygen, sulfur or H₂, R⁵ is hydrogen oralkyl, and the nitrogen is attached to the pyridinyl ring);

R¹ is halo or haloalkyl;

R² is hydrogen, haloalkyl, or --OR⁵ where R⁵ is hydrogen or alkyl;

R³ is a radical of the formula (i): ##STR16##

where r is 1;

R¹³ is halo; and

each R¹⁴ is independently hydrogen, alkyl, halo, formyl, acetyl, cyano,--R⁸ --CN, --N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸ --N(R¹⁰)R¹¹,--C(R⁷)H--N.sup.⊕ (R⁹)(R⁹)₂, --C(R⁷)H--R⁸ --N.sup.⊕ (R⁹)(R¹⁶)₂,--C(O)OR⁵, --C(R⁷)H--C(O)OR⁵, --C(R⁷)H--R⁸ --C(O)OR₅, --OR⁵,--C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--O--R¹⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --C(R⁷)H--S(O)_(p) --R¹⁵ (where p is 0 to 2),--C(R⁷)H--R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2), --S(O)_(p) --N(R⁵)R⁶(where p is 0 to 2), --C(O)N(R⁵)R⁶, --C(R⁷)H--C(O)N(R⁵)R⁶, --C(R⁷)H--R⁸--C(O)N(R⁵)R⁶, --C(R⁷)H--N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--R⁸ --N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --C(R⁷)H--R⁸--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --O--R⁸ --CH(OH)--CH₂ --OR⁵,--C(R⁷)H--O--R⁸ --CH(OH)--CH₂ --OR⁵, --C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t)--CH₂ --OR⁵ (where t is 1 to 6), --C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰,--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--O--N(R⁵)R⁶,heterocyclyl (wherein the heterocyclyl radical is not attached to theradical of formula (i) through a nitrogen atom and is optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (whereinthe heterocyclyl radical is not attached to the alkyl radical through anitrogen atom and is optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); where R⁵and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁷ is independently hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyll aryl or aralkyl;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, haloalkyl, aryl,aralkyl, formyl, cyano, --R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2),--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸--C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, --R--N(R⁵)--C(O)H, --R⁸-N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, --R⁸--N(R⁵)--P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), where

R⁵ and R⁵ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁵ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵,

--R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

or R⁵ and R¹⁵ together with the nitrogen to which they are attached forma N-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl, where

each R⁵ is hydrogen, alkyl, aryl or aralkyl; and

R¹⁸ is hydrogen, alkyl, aryl, aralkyl, cyano, --C(O)OR⁵, or --NO₂ ;

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, halo,haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸ --CN, ═N(R¹⁷), --OR⁵,--C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶,--R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1to 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶, where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R¹⁶ is independently alkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁸--N(R⁵)R⁶, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain; or

both R¹⁶ 's together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubsfituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)R⁵,--C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸ --O)_(t) --R⁵(where t is 1 to 6), where

R⁵ and R⁶ are independently each hydrogen, alksyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶, where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

and R⁴ is hydrogen or halo.

Of this group of compounds, a preferred subgroup of compounds are thosecompounds wherein:

m is 1;

n is 1;

D is --N(H)--C(O)--;

E is --C(O)--N(H)-- (where the nitrogen is bonded to the 2-position ofthe pyridinyl ring);

R² is hydrogen, haloalkyl, or --OR⁵ where R⁵ is hydrogen or alkyl;

R³ is a radical of the formula (i): ##STR17##

where r is 1;

R¹³ is halo; and

R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where:

R⁷ is hydrogen;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, haloalkyl, aryl,aralkyl, formyl, cyano, --R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2),--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸--C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸--N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, --R⁸--N(R⁵)--P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

or R⁵ and R¹⁵ together with the nitrogen to which they are attached forma N-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl, where

each R⁵ is hydrogen, alkyl, aryl or aralkyl; and

R¹⁸ is hydrogen, alkyl, aryl, aralkyl, cyano, --C(O)OR⁵, or --NO₂ ;

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, halo,haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸ --CN, ═N(R¹⁷), --OR⁵,--C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶,--R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1to 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), where

R⁶ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶ where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

and R⁴ is in the 5-position.

Of this subgroup of compounds, a preferred class of compounds are thosecompounds wherein:

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, haloalkyl, aryl,aralkyl, formyl, cyano, --R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2),--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸--C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸--N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, --R⁸--N(R⁵)--P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--N(R⁵)R⁶ and --C(O)N(R⁵)R⁸), where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶) where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

or R⁵ and R¹⁵ together with the nitrogen to which they are attached forma N-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl, where

each R⁵ is independently hydrogen, alkyl, aryl or aralkyl; and

R¹⁸ is hydrogen, alkyl, aryl, aralkyl, cyano, --C(O)OR⁵, or --NO₂.

Of this class of compounds, a preferred subclass of compounds are thosecompounds wherein:

R¹⁰ is hydrogen, alkyl, or --R⁸ --OR⁵ ; and

R¹¹ is hydrogen, alkyl or --R⁸ --OR⁵ ;

where each R⁸ is independently a straight or branched alkylene chain,and each R⁵ is hydrogen or alkyl.

Of this subclass of compounds, preferred compounds are those compoundsselected from the group consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N',N'-di(2-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2,2-dimethyl-2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-ethoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yi)-2-1((4-(((2-hydroxyethyi)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-methylethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(ethylaminomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-(diethylamino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Of this class of compounds, another preferred subclass of compounds arethose compounds wherein:

R¹⁰ is hydrogen, alkyl, or --R⁸ --N(R⁵)R⁶, and

R¹¹ is --S(O)_(p) --R¹⁵ (where p is 0 to 2) or --R⁸ --N(R⁵)R⁶ where:

R⁵ and R⁶ are independently hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain; and

R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, --R⁸--O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,heterocyclyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶),or heterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁶)R⁶)where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain.

Of this subclass of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(methyl)sulfonyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((3,5-dimethylisoxazol-4-yl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((2-(4-hydroxypiperidin-1-yl)ethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-aminoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(4-(dimethylamino)but-3-yn-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Of this class of compounds, another preferred subclass of compound arethose compounds wherein:

R¹⁰ is hydrogen, alkyl or --R⁸ --OR⁵ ; and

R¹¹ is formyl, cyano, --C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵,--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--P(O)(OR⁵)₂, or--C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, where:

each R⁵ is hydrogen or alkyl;

R⁸ is a straight or branched alkylene chain;

each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶) where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain; and

R¹⁸ is hydrogen, alkyl, aryl, aralkyl, cyano, --C(O)OR⁵, or --NO₂.

Of this subclass of compounds, preferred compounds are those compoundsselected from the group consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-carboxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-(morpholin-4-yl)ethyl)thioureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(((4-hydroxypiperidin-1-yl)methyl)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-hydroxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(N'-methylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-hydroxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-(chloro)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-(acetoxy)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-(pyrrotidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-(chloro)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-(((2-hydroxyphenyl)carbonyl)oxy)ethyl)ureido)-methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-cyanoamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-((fluoromethylcarbonyl)amino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((2-aminoethoxy)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((methylthio)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-((phenylthio)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-nitro-1-(methylamino)ethenyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((2-dimethylphosphoramidoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Of the class of compounds, another preferred subclass of compounds arethose compounds wherein:

R¹⁰ is hydrogen, alkyl, haloalkyl, or --R⁸ --OR⁵ ;

R¹¹ is cycloalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo and --OR⁵),heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹ (where pis 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶ or--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--N(R⁵)R⁵ and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁶, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶) where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain.

Of this subclass of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-(morpholin-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-hydroxycyclohexyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(6-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(pyridin-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)aminol-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(thiazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyrldin-2-yl)-2-[((4-((N'-ethyl-N'-(thiazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-(oxo)oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(pyridin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(dihydro-4(H)-1,3-oxazin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(t-butyl)-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((thiazol-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-methoxyethyl)-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(oxazol-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-trifluoromethyl-5-(methoxycarbonyl)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(dihydro-4(H)-1,3-oxazin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(5-methyloxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(tetrazol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(tetrazol-5-yl)amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(4-methyloxazolin-2-yl)amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(pyrazol-3-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2,2,2-trifluoroethyl)-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(4-(ethoxycarbonyl)oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1,2,4-triazol-4-yl)amino)methyl)-3-chiorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(pyridin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-amino-6-methylpyrimidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((1,2,4-oxadiazol-3-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-(imidazol-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3,4,5,6-tetrahydropyridin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-chloropyrimidin4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(imidazol-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-aminopyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(4-aminopyrimidin-2-yl)amino)methyl)-3-chiorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(4-(methylamino)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((3-((methylthio)methyl)-1,2,4-oxadiazol-5-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1,3,2-dioxaphospholan-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Of the subgroup of compounds, another preferred class of compounds arethose compounds wherein:

R¹⁰ and R¹¹ together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸ --CN, ═N(R¹⁷), --OR⁵,--C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁶)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶,--R⁸ --C(O)N(R⁵)R⁵, --N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1to 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶ where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain.

Of this class of compounds, a preferred subclass of compounds are thosecompounds wherein the N-heterocylic ring is optionally substituted byone or more substituents selected from the group consisting of alkyl,halo, haloalkyl, aryl, aralkyl, and nitro.

Of this subclass of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((4,5-dihydropyrazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((morpholin-4-ylemethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((pyrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((hydantoin-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((1,4,5,6-tetrahydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((pyrrolidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2,3,4,5,6,7-hexahydro-3,7-dimethyl-2,6-dioxo-1H-purin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(pyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(5-bromopyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)aminol-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((5-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2,4-dimethylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2,5-dimethylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)aminol-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-methyl-4-nitroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4,5-dichloroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(chloromethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((2-(fluoromethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Of the class of compounds, another preferred subclass of compounds arethose compounds wherein the N-heterocylic ring is substituted by one ormore substituents selected from the group consisting of alkyl, nitro,--R⁸ --CN, --OR⁵, --N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --S(O)_(p) --R⁹ (where pis 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and heterocyclyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl.

Of this subclass of compounds, preferred compounds are those compoundsselected from the group consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((4-(hydroxymethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((5-(hydroxymethyl)imidazol-1-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(methoxymethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(hydroxymethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-formylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(N'-amino-N-methyl)amino)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-hydroxypiperidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylthio)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-(methylsulfonyl)piperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-methyl4-nitroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(cyanomethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Of the class of compounds, another preferred subclass of compounds arethose compounds wherein the N-heterocylic ring is substituted by one ormore substituents selected from the group consisting of alkyl, oxo,═N(R¹⁷), --C(O)OR⁵, --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, --(R⁸ --O)_(t) --R⁵, andheterocyclyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, or --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, --R⁸--C(O)--N(R⁵)R⁶ where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain.

Of this subclass of compounds, preferred compounds are those wherein theN-heterocylic ring is substituted by ═N(R¹⁷) and is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, oxo, --C(O)OR⁵, --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, and --(R⁸--O)_(t) --R⁵, where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶ where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain.

Of these compounds, preferred compounds are selected from the groupconsisting of:

N-(5--chloropyridin-2-yl)-2-[((4-((2-imino-5-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5,5-(dimethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-ethylimino-5,5-(dimethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(S)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(R)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((24iminotetrahydrooxazol-3-yl)methyl)-3-chiorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5-(methoxymethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((trans4,5-dimethyl-2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((cis-4,5-dimethyl-2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((3-methyl-2-imino-2,3-dihydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-1,2-dihydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-(hydroxymethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrothiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-oxoimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyi)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((tetrahydro-2-imino-2H-pyrimidin-1-ylpyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(methoxycarbonylamino)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(cyanoimino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-3-((phenylamino)carbonyl)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-((4-((cis-4,5-dimethoxy-2-iminotetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-4-imino-1,4-dihydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-((2-hydroxyethyl)imino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-iminopiperidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-imino-1(4H)-pyridinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-1(2H)-pyridin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylimino)pyrrolidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((2-(((aminocarbonyl)methyl)imino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amina]-3-methoxy-5-chlorobenzamide.

Of the class of compounds, another preferred subclass of compounds arethose compounds wherein the N-heterocylic ring is substituted by--N(R⁵)R⁶ and optionally substituted by one or more substituentsselected from the group consisting of alkyl, oxo, --N(R⁵)R⁶, --OR⁵, and--C(O)N(R⁵)R⁶, where R⁵ and R⁶ are each independently hydrogen, alkyl,aryl or aralkyl.

Of this subclass of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((5-aminotetrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((3-amino-1,2,4-triazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((3,5-diamino-4H-1,2,4-triazol-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-amino-5-(aminocarbonyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2,6-diaminopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2,6-diaminopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chlordpyridin-2-yl)-2-[((4-((5-amino-2-oxo-2H-pyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(6-chloropyridin-2-yl)-2-[((4-((6-aminopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((6-aminopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-6-oxopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-6-oxopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((5-(dimethylamino)-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((5-amino-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2,4-diamino-6-hydroxypyrimidin-5-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(1-methylethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((3-dimethylamino-5-methylpyrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((3-dimethylamino-5-methylpyrazol-2-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Of the group of compounds described above, another preferred subgroup ofcompounds are those compounds wherein:

each R¹⁴ is independently alkyl, --R⁸ --CN, --C(R⁷)H--R⁸ --N(R¹⁰)R¹¹,--C(R⁷)H--R⁸ --N.sup.⊕ (R⁹)(R¹⁶)₂, --C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵,--C(R⁷)H--O--R¹⁵, --C(R⁷)H--S(O)_(p) --R¹⁵ (where p is 0 to 2),--C(R⁷)H--N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t) --CH₂ --OR⁵ (where t is 1 to 6),--C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹, --C(R⁷)H--O--N(R⁵)R⁶, orheterocyclyl (wherein the heterocyclyl radical is not attached to theradical of formula (i) through a nitrogen atom and is optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁷ is independently hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, haloalkyl, aryl,aralkyl, formyl, cyano, --R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2),--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸--C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸--C(O)--N(R⁵)R¹⁵, C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸--N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, --R⁸--N(R⁵)--P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

or R⁵ and R¹⁵ together with the nitrogen to which they are attached forma N-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonylmonoalkylaminocarbonyl, and dialkylaminocarbonyl, where

each R⁵ is hydrogen, alkyl, aryl or aralkyl; and

R¹⁸ is hydrogen, alkyl, aryl, aralkyl, cyano, --C(O)OR⁵, or --NO₂ ;

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, halo,haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸ --CN, ═N(R¹⁷), --OR⁵,--C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶,--R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1to 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), where

R⁵ and R⁵ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶, where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R¹⁶ is independently alkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁸--N(R⁵)R⁶, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alky, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁶, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain; or

both R¹⁶ 's together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --R--C(O)OR⁵, --N(R⁵)R⁶, --R--N(R⁵)R⁶,--C(O)R⁵, --C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸--O)_(t) --R⁵ (where t is 1 to 6), where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain.

Of this subgroup of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((pyridinium-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide,

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(hydroxyethoxy)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((methylsulfinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((2-hydroxyethyl)sulfinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((pyridinium-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-cyanomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(2-methylaminoethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(hydroxy)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((imidazol-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((imidazolin-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((5-hydroxymethyl-1-methylimidazol-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((diethylamino)oxy)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;and

N-(5-chioropyridin-2-yl)-2-[((4-(imidazolin-2-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Of the group of comounds described above, another preferred subgroup ofcompounds are those compounds wherein:

each R¹⁴ is independently --C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰, or --C(R⁷)H--C(NR¹⁷)--N(R⁵)R⁶, where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁷ is independently hydrogen or alkyl;

each R⁹ is independently alkyl, aryl or aralkyl;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, haloalkyl, aryl,aralkyl, formyl, cyano, --R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2),--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, 13 R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸--C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸--N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, --R⁸--N(R⁵)--P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

or R⁵ and R¹⁵ together with the nitrogen to which they are attached forma N-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl, where

each R⁵ is hydrogen, alkyl, aryl or aralkyl; and

R¹⁸ is hydrogen, alkyl, aryl, aralkyl, cyano, --C(O)OR⁵, or --NO₂ ;

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, halo,haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸ --CN, ═N(R⁷), --OR⁵,--C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶,--R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t) R⁵(where t is 1 to 6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1to 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), where

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R⁹ is independently alkyl, aryl or aralkyl;

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶, where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain;

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶, where

R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and

each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain.

Of this subgroup of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-(((amidino)(methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-iminoethyl)-N'-methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(N'-N"-dimethyl-N"'-cyanoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(N'-methyl-N"-hydroxyguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(N'-methyl-N"-(2-aminoethyl)-N"'-cyanoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(N'-methyl-N"-aminoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(N'-N"-dimethyl-N"'-(aminocarbonyl)guanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(imino(phenyl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-imino-2-(aminocarbonyl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-imino-4,4,4-trifluorobutyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(imino(pyridin4-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(imino(thiophen-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(imino(pyrazin-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(cyclopropyl(imino)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(3-cyano-1-iminopropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-imino-4,4,4-trifluorobutyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-(2-amino-2-(hydroxyimino)ethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Of the compounds of formula (I) described above, another preferred groupof compounds are those compounds of formula (I) wherein:

A is ═N--;

m is 1;

n is 1;

D is --N(H)--C(O)--;

E is --C(O)--N(H)-- (where the nitrogen is bonded to the 2-position ofthe pyridinyl ring);

R² is --N(R¹⁰)R¹¹ where:

R¹⁰ and R¹¹ are each independently hydrogen, alkyl or --R⁸ --O--R⁵ whereR⁸ is an alkylene chain, and R⁵ is hydrogen or alkyl; or

R¹⁰ and R¹¹ together with the nitrogen to which they are attached form aN-heterocyglic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl and --C(O)OR⁵where R⁵ is hydrogen or alkyl;

R³ is a radical of the formula (i): ##STR18##

where r is 1;

R¹³ is halo; and

R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ or --C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t) --CH²--OR⁵ (where t is 1 to 3)

where:

each R⁵ is independently hydrogen or alkyl;

R⁷ is hydrogen;

R⁸ is a straight or branched alkylene chain;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, formyl, --R⁸ --OR⁵,--S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,--C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂, --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵,cycloalkyl (optionally substituted by --OR⁵), heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, haloalkyl, oxo, --OR⁵, and --C(O)OR⁵), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, haloalkyl, oxo, --OR⁵, and--C(O)OR⁵), where:

each R⁵ and R⁶ is independently hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene chain; and

each R¹⁵ is alkyl, --R⁸ --OR⁵, --R⁸ --C(O)OR⁵, heterocyclyl (optionallysubstituted by --R⁸ --OR⁵), or heterocyclylalkyl (optionally substitutedby --OR⁵);

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, oxo,═N(R¹⁷), --OR⁵, --R⁸ --OR⁵, and --N(R⁵)R⁶ ; where

each R⁵ and R⁶ is independently hydrogen or alkyl;

R⁸ is a straight or branched alkylene chain; and

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶ ;

and R⁴ is in the 5-position and is hydrogen or halo.

Of this group of compound, a preferred subgroup of compounds are thosecompounds wherein:

R² is --N(R¹⁰)R¹¹ where:

R¹⁰ and R¹¹ are each independently hydrogen, alkyl or --R⁸ --O--R⁵ whereR⁸ is an alkylene chain, and R⁵ is hydrogen or alkyl.

Of this subgroup of compounds, a preferred class of compounds are thosecompounds wherein:

R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where:

R⁷ is hydrogen;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, formyl, --R⁸ --OR⁵,--S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,--C(O)--R₁₅, --C(O)NH₂, --C(S)NH₂, --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵,cycloalkyl (optionally substituted by --OR⁵), heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, haloalkyl, oxo, --OR⁵, and --C(O)OR⁵), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, haloalkyl, oxo, --OR⁵, and--C(O)OR⁵); where:

each R⁵ and R⁶ is hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene chain; and

each R¹⁵ is alkyl, --R⁸ --OR⁵, --R⁸ --C(O)OR⁵, heterocyclyl (optionallysubstituted by --R⁸ --OR5), or heterocyclylalkyl (optionally substitutedby --OR⁵);

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, oxo,═N(R¹⁷), --OR⁵, --R⁸ --OR⁵, and --N(R⁵)R⁶ ; where:

each R⁵ is hydrogen or alkyl;

R⁸ is straight or branched alkylene chain; and

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶.

Of this class of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(di(2-methoxyethyl)amino)-5-chlorobenzamide.

Of this group of compounds, another preferred subgroup of compounds arethose compounds wherein:

R² is --N(R¹⁰)R¹¹ where:

R¹⁰ and R¹¹ together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl and --C(O)OR⁵where R⁵ is hydrogen or alkyl.

Of this subgroup of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-g((4-((N'-methyl-N'-(2-(morpholin-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-methoxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methylsulfonyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N"-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolidin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-methylethyl)-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(ethoxycarbonyl)piperidin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(carboxy)piperidin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-1((4-((N'-methyl-N'-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-ethylpiperazin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-trifluoromethyl-5-(methoxycarbonyl)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-trifluoromethyl-5-carboxypyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(tetrazol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin4-yl)-5-chlorobenzamide.

Of the compounds of formula (I) described above, another preferred groupof compounds are those compounds of formula (I) wherein:

A is ═N--;

m is 1;

n is 1;

D is --N(H)--C(O)--;

E is --C(O)--N(H)-- (where the nitrogen is bonded to the 2-position ofthe pyridinyl ring);

R² is --O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 3) or --O--(R⁸ --O)_(t)--R¹⁹ where R⁵ is hydrogen or alkyl, each R⁸ is independently a straightor branched alkylene chain, and R¹⁹ is heterocyclyl (optionallysubstituted by alkyl, aryl, aralkyl, halo, or haloalkyl);

R³ is a radical of the formula (i): ##STR19##

where r is 1;

R¹³ is halo; and

R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where:

R⁷ is hydrogen;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, formyl, --R⁸ --OR⁵,--S(O)R_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,--C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂, --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵,cycloalkyl (optionally substituted by --OR⁵), heterocyclyl (optionallysubstituted by one or more substituents selected from--the groupconsisting of alkyl, haloalkyl, oxo, --OR⁵, and --C(O)OR⁵), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, haloalkyl, oxo, --OR⁵, and--C(O)OR⁵); where:

each R⁵ and R⁶ is hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene chain; and

each R¹⁵ is alkyl, --R⁸ --OR⁵, --R⁸ --C(O)OR⁵, heterocyclyl (optionallysubstituted by --R⁸ --OR⁵), or heterocyclylalkyl (optionally substitutedby --OR⁵);

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, oxo,═N(R¹⁷), --OR⁵, --R⁸ --OR⁵, and --N(R⁵)R⁶ ; where

each R⁵ is hydrogen or alkyl;

R⁸ is straight or branched alkylene chain; and

each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶ ; and

R⁴ is in the 5-position and is hydrogen or halo.

Of this group of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyridin-3-yloxy)propoxy)-5-chlorobenzamide.

Of the compounds of formula (I) described above, another preferred groupof compounds are those compounds of formula (I) wherein:

A is ═N--;

m is 1;

n is 1;

D is --N(H)--C(O)--;

E is --C(O)--N(H)-- (where the nitrogen is bonded to the 2-position ofthe pyridinyl ring);

R² is --O--R⁸ --N(R¹⁰)R¹¹ where:

R⁸ is a straight or branched alkylene chain; and

R¹⁰ and R¹¹ are each independently hydrogen, alkyl or --R⁸ --O--R⁵ whereR⁸ is an alkylene chain, and R⁵ is hydrogen or alkyl; or

R¹⁰ and R¹¹ together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl and --C(O)OR⁵where R⁵ is hydrogen or alkyl;

R³ is a radical of the formula (i): ##STR20##

where r is 1;

R¹³ is halo; and

R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where:

R⁷ is hydrogen;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, formyl, --R⁸ --OR⁵,--S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,--C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂, --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵,cycloalkyl (optionally substituted by --OR⁵), heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, haloalkyl, oxo, --OR⁵, and --C(O)OR⁵), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, haloalkyl, oxo, --OR⁵, and--C(O)OR⁵), where:

each R⁵ and R⁶ is hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene chain; and

each R¹⁵ is alkyl, --R⁸ --OR⁵, --R⁸ --C(O)OR⁵, heterocyclyl (optionallysubstituted by --R⁸ --OR⁵), or heterocyclylalkyl (optionally substitutedby --OR⁵); and

R⁴ is in the 5-position and is hydrogen or halo.

Of this group of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chloroberizamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(imidazol-1-yl)ethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(imidazol-1-yl)propoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(pyrrolidin-1-yl)ethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(imidazol-1-yl)ethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(pyrrolidin-1-yl)ethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsuffonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(4-ethylpiperazin-1-yl)propoxy)-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-aminoethoxy)-5-chlorobenzamide.

Of the compounds of formula (I) described above, another preferred groupof compounds are those compounds of formula (I) wherein:

A is ═N--;

m is 1;

n is 1;

D is --N(H)--C(O)--;

E is --C(O)--N(H)-- (where the nitrogen is bonded to the 2-position ofthe pyridinyl ring);

R² is --O--R⁸ --O--C(O)R⁵, --O--R⁸ --CH(OH)--CH₂ --N(R¹⁰)R¹¹, or --O--R⁸--CH(OH)--CH₂ --OR⁵ where

each R⁵ is hydrogen or alkyl;

R⁸ is a straight or branched alkylene chain; and

R¹⁰ and R¹¹ are each independently hydrogen, alkyl or --R⁸ --O--R⁵ whereR⁸ is an alkylene chain, and R⁵ is hydrogen or alkyl; or

R¹⁰ and R¹¹ together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl and --C(O)OR⁵where R⁵ is hydrogen or alkyl;

R³ is a radical of the formula (i): ##STR21## where r is 1;

R⁻⁻ is halo; and

R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ or --C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹ where:

R⁵ is hydrogen or alkyl;

R⁷ is hydrogen;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, formyl, --R⁸ --OR⁵,--S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,--C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂, --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵,cycloalkyl (optionally substituted by --OR⁵), heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, haloalkyl, oxo, --OR⁵, and --C(O)OR⁵), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, haloalkyl, oxo, --OR⁵, and--C(O)OR⁵); where:

each R⁵ and R⁶ is hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene chain; and

each R¹⁵ is alkyl, --R⁸ --OR⁵, --R⁸ --C(O)OR⁵, heterocyclyl (optionallysubstituted by --R⁸ --OR⁵), or heterocyclylalkyl (optionally substitutedby --OR⁵); and

R⁴ is in the 5-position and is hydrogen or halo.

Of this group of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-acetoxyethoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(imidazol-1-yl)propoxy)-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-methoxypropoxy)-5-chlorobenzamide.

Of the compounds of formula (I) described above, another preferred groupof compounds are those compounds of formula (I) wherein:

A is ═N--;

m is 1 to 3;

n is 1;

D is --N(R⁵)--C(Z)-- (where Z is oxygen and R⁵ is hydrogen or alkyl);

E is --C(Z)--N(R⁵)-- (where Z is oxygen, R⁵ is hydrogen or alkyl, andthe nitrogen is attached to the pyridinyl ring);

each R¹ is independently hydrogen, halo or --OR⁵ ; or two adjacent R¹ 'stogether with the carbons to which they are attached form a dioxole ringfused to the phenyl ring wherein the dioxole ring is optionallysubstituted by alkyl;

R² is hydrogen;

R³ is a radical of the formula (i): ##STR22##

where r is 1;

R¹³ is halo; and

R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where:

R⁷ is hydrogen; and

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, formyl, --R⁸ --OR⁵,--S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,--C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂, --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵,cycloalkyl (optionally substituted by --OR⁵), heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, haloalkyl, oxo, --OR⁵, and --C(O)OR⁵), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, haloalkyl, oxo, --OR⁵, and--C(O)OR⁵); where:

each R⁵ and R⁶ is hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene chain; and

each R¹⁵ is alkyl, --R⁸ --OR⁵, --R⁸ --C(O)OR⁵, heterocyclyl (optionallysubstituted by --R⁸ --OR⁵), or heterocyclylalkyl (optionally substitutedby --OR⁵); and

R⁴ is in the 5-position and is hydrogen or halo.

Of this group of compounds, preferred compounds are selected from thegroup consisting of:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3,4,5-trimethoxybenzamide;

(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole;

5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole;and

5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N'-(2-methoxyethyl)-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole.

Of the compounds of formula (I) described above, another preferred groupof compounds are those compounds of formula (I) wherein:

A is --CH--;

m is 1;

n is 1;

D is --N(R⁵)--C(Z)-- (where Z is oxygen and R⁵ is hydrogen or alkyl);

E is --C(Z)--N(R⁵)-- (where Z is oxygen, R⁵ is hydrogen or alkyl, andthe nitrogen is attached to the phenyl ring having the R⁴ substituent);

R¹ is alkyl or halo;

R² is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, --OR⁵,--S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵, --C(O)N(R⁵)R⁶,--N(R¹⁰)R¹¹, --C(R⁷)H--OR⁵, --C(R⁷)H--S(O)_(p) --R⁹ (where p is 0 to 2),--O--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --C(R⁷)H--N(R⁵)R⁶, --O--R⁸--CH(OH)--CH₂ --N(R¹⁰)R¹¹, --O--R⁸ --N(R¹⁰)R¹¹, --O--R⁸ --O--C(O)R⁵,--O--R⁸ --CH(OH)--CH₂ --OR⁵ ; O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--O--R⁸ --C(O)R⁵, --O--R⁸ --C(O)OR⁵, --N(R⁵)--R⁸ --N(R¹⁰)R¹¹, --S(O)_(p)R⁸ --N(R⁵)R⁶ (where p is 0 to 2), --S(O)_(p) --R⁸ --C(O)OR⁵ (where p is0 to 2), --N(R⁵)--CH(R¹²)--C(O)OR⁵ ;

R³ is a radical of formula (i): ##STR23## where:

r is 1 or 2;

R¹³ is hydrogen, alkyl, halo, haloalkyl, --N(R⁵)R⁶, --C(R⁷)H--N(R⁵)R⁶,--OR⁵, --S(O)_(p) --R⁸ --N(R⁵)R⁶ (where p is 0 to 2) orheterocyclylalkyl (where the heterocyclic ring is optionally substitutedby one or more substituents selected from the group consisting of alkyl,halo, aralkyl, nitro and cyano); and

each R¹⁴ is independently hydrogen, alkyl, halo, formyl, acetyl,--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--N.sup.⊕ (R⁹)(R¹⁶)₂,--N(R⁵)--R⁸ --C(O)OR⁵, --C(R⁷)H--N(R⁵)--R⁸ --C(O)OR⁵, --C(O)OR⁵, --OR⁵,--C(R⁷)H--OR⁵, --S(O)_(p) R¹⁵ (where p is 0 to 2), --C(R⁷)H--S(O)_(p)--R¹⁵ (where p is 0 to 2), --S(O)_(p) --N(R⁵)R⁶ (where p is 0 to 2),--C(O)N(R⁵)R⁶, --C(R⁷)H--N(R⁵)--(R⁸ --O)_(t) R⁵ (where t is 1 to 6),--C(R⁷)H--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --O--R⁸--CH(OH)--CH₂ --OR⁵, --C(R⁷)H--O--R⁸ --CH(OH)--CH₂ --OR⁵,--C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t) --CH₂ --OR⁵ (where t is 1 to 6),--C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹, or --C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰;

R⁴ is halo;

R⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;

R⁷ is hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene or alkylidenechain;

each R⁹ is independently alkyl, aryl or aralkyl;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, aryl, aralkyl,formyl, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸--N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂,--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, cycloalkyl (optionally substitutedby one or more substituents selected from the group consisting of alkyl,halo and --OR⁵), heterocyclyl (optionally substituted by alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁵, and--C(O)N(R⁵)R⁶);

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, oxo, ═N(R¹⁷), --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t) R⁵ (where t is 1 to 6), and--(R⁸ --O)_(t) R⁵ (where t is 1 to 6);

R¹² is a side chain of an α-amino acid;

each R¹⁵ is independently alkyl, haloalkyl, aryl, aralkyl, --R --OR⁵,--R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, heterocyclyl (optionally substituted byone or more substituents selected from the group consisting of alkyl,aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶);

or R⁵ and R¹⁵ together with the nitrogen to which they are attached forma N-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl; and

each R¹⁶ is independently alkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁸--N(R⁵)R⁶, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), or

both R¹⁶ 's together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)R⁵,--C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸ --O)_(t) --R⁵(where t is 1 to 6).

Of this group of compounds, a preferred subgroup of compounds are thosecompounds wherein:

D is --N(H)--C(O)--;

E is --C(O)--N(H)--;

R¹ is halo;

R² is hydrogen, --OR⁵, --N(R¹⁰)R¹¹, --O--R⁸ --S(O)_(p) --R⁹ (where p is0 to 2), --O--R⁸ --N(R¹⁰)R¹¹, --O--R⁸ --O--C(O)R⁵ or --O--R⁸ --C(O)OR⁵where:

each R⁵ is hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene chain;

R⁹ is alkyl;

R¹⁰ and R¹¹ together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms;

R³ is a radical of formula (i): ##STR24## where:

r is 1;

R¹³ is halo; and

R¹⁴ is in the 4-position and is --C(R⁷)H--N(R¹⁰)R¹¹ where:

R⁷ is hydrogen or alkyl; and

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, --R⁸ --OR⁵ orheterocyclyl;

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a piperazine ring optionally substituted by alkyl; and

R⁴ is chloro.

Of this subgroup of compounds, preferred compounds are selected from thegroup consisting of:

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-fluorobenzamide;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxy-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((acetoxy)ethoxy)-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(morpholin-4-yl)ethoxy)-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((methylthio)methoxy)-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;and

N-(4-chlorophenyl)-2-[((4((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Of the group of compounds described above, another preferred subgroup ofcompounds are those compounds wherein:

D is --N(H)--C(O)--;

E is --C(O)--N(H)--;

R¹ is methyl or chloro;

R² is hydrogen or --OR⁵ ;

R³ is a radical of formula (i): ##STR25## where:

r is 1 or 2;

R¹³ is alkyl, halo, OR⁵ (where R⁵ is alkyl) or heterocyclylalkyl (wherethe heterocyclic ring is optionally substituted by alkyl); and

each R¹⁴ is independently hydrogen, alkyl, halo, formyl, --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--N.sup.⊕ (R⁹)(R¹⁶)₂, --C(O)OR⁵,--C(R⁷)H--OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --C(R⁷)H--S(O)_(p)--R¹⁵ (where p is 0 to 2), --C(O)N(R⁵)R⁶, --C(R⁷)H--N(R⁵)--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), --C(R⁷)H--O--(R⁸ --O)_(t) --R⁵ (where t is 1to 6),

--C(R⁷)H--O--R⁸ --CH(OH)--CH₂ --OR⁵, or --C(R⁷)H--N(R⁵)--R⁸--[CH(OH)]_(t) --CH₂ --OR⁵ (where t is 1 to 6);

R⁴ is halo;

R⁵ and R⁶ are each independently hydrogen or alkyl;

each R⁷ is independently hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene chain;

R⁹ is alkyl;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, aryl, aralkyl,formyl, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) R¹⁵ (where p is 0 to 2), --R⁸--N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂,--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, heterocyclyl (optionally substitutedby alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶ or--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substitutedby one or more substituents selected from the group consisting of alkyl,aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and--C(O)N(R⁵)R⁶);

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, oxo,--N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)R⁵, and --C(O)--(R⁸ --O)_(t) --R⁵(where t is 1 to 6);

R¹⁵ is alkyl, haloalkyl, aryl, aralkyl, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸--N(R⁵)R⁶ --R⁸ --C(O)OR⁵, heterocyclyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁶, --N(R⁵)R⁶),and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶);

or R⁵ and R¹⁵ together with the nitrogen to which they are attached forma N-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl; and

each R¹⁶ is independently alkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁸--N(R⁵)R⁶, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), or

both R¹⁶ 's together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)R⁵,--C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸ --O)_(t) --R⁵(where t is 1 to 6).

Of this subgroup of compounds, a preferred class of compounds are thosecompounds wherein:

R³ is a radical of formula (i): ##STR26## where:

r is 1 or 2;

R¹³ is halo, alkyl or 4-methylpiperazin-1-yl, and

each R¹⁴ is independently hydrogen or --C(R⁷)H--N(R¹⁰)R¹¹ where:

R⁷ is hydrogen or alkyl;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, aryl, aralkyl,formyl, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸--N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂,--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, heterocyclyl (optionally substitutedby alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶) where:

each R⁵ and R⁶ are independently hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene chain; and

each R¹⁵ is alkyl, haloalkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁸ --N(R⁵)R⁶,--R⁸ --C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶).

Of this class of compounds, preferred compounds are selected from thegroup consisting of:

N-(4-chlorophenyl)-2-[((3-methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((5-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(N'-methyl-N'-(2-hydroxyethyl)amino)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(N'-methyl-N'-(ethoxycarbonylmethyl)amino)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(N'-methyl-N'-(carboxymethyl)amino)methylthiophen-2yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(N',N'-di(2-hydroxyethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(((N'-(3-dimethylaminophenyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4,5-di((n-propyl)aminomethyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-((N'-methyl-N'-(2-dimethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(ethoxycarbonylmethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2-dimethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-(3-(imidazol-1-yl)propyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(3-(dimethylamino)propyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloror-((N'-(2-methylpropyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(1-methylpiperidin4-yl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-(2-(morpholin-4-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-hydroxyamino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2-diethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-(2-hydroxyethyl)1-N'-(2-(morpholin-4-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;and

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.

Of the subgroup of compounds described above, another preferred class ofcompounds are those compounds wherein:

R³ is a radical of formula (i): ##STR27## where:

r is 1 or 2;

R¹³ is halo or alkyl, and

each R¹⁴ is independently hydrogen, alkyl or --C(R⁷)H--N(R¹⁰)R¹¹ where:

R⁷ is hydrogen or alky; and

R¹⁰ and R¹¹ together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, oxo,--N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)R⁵, and --C(O)--(R⁸ --O)_(t) R⁵

(where t is 1 to 6) where

each R⁵ is hydrogen or alkyl; and

R⁸ is a straight or branched alkylene chain.

Of this class of compounds, preferred compounds are selected from thegroup consisting of:

N-(4-chlorophenyl)-2-[((4-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-((4-(carboxymethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((5-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-((4-(ethoxycarbonylmethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonylamino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(morpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(1-(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-((4-(((2-(2-methoxyethoxy)ethoxy)methyl)carbonyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-(morpholin-4-yl)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(1,1,4-tri(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-methyl-4-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro4-methyl-5-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((4H-1,2,4-triazol-1-yl)methyl)thiophen-2-yI)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((tetrazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((tetrazol-2-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((pyrazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,3-triazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,3-triazol-2-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((4-ethylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((4-oxomorpholin-4-yl)methyl)thiophen-2-yl)carbonyle)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((4-acetylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;and

N-(4-chlorophenyl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Of this subgroup of compounds described above, another preferred classof compounds are those compounds wherein:

R³ is a radical of formula (i): ##STR28## where:

r is 1 or 2;

R¹³ is halo or alkyl, and

each R¹⁴ is independently --C(R⁷)H--S(O)_(p) --R¹⁵ where:

p is 0 to 2;

R⁷ is hydrogen or alkyl; and

R¹⁵ is alkyl, --R⁸ --N(R⁵)R⁶ or --R⁸ --C(O)OR⁵ where:

R⁵ and R⁶ are each independently hydrogen or alkyl; and

each R⁸ is independently a straight or branched alkylene chain.

Of this class of compounds, preferred compounds are selected from thegroup consisting

N-(4-chlorophenyl)-2-[((3-chloro-5-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(((methoxycarbonylmethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(((methoxycarbonylmethyl)sulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-((methylsulfinyl)methyl)thiophen-2-yl)carbonyle)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(((carboxymethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-((methylsulfonyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(((2-(dimethylamino)ethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(((2-(dimethylamino)ethyl)sulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-(((methoxycarbonylmethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-(((2-(dimethylamino)ethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((methylsulfonyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;and

N-(4-chlorophenyl)-2-[((3-chloro-4-((methylsulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.

Of the subgroup of compounds described above, another preferred class ofcompounds are those compounds wherein:

R³ is a radical of formula (i): ##STR29## where:

r is 1 or 2;

R¹³ is halo or alkyl, and

each R¹⁴ is independently formyl, --N(R¹⁰)R¹¹, --C(O)OR⁵, --C(R⁷)H--OR⁵or --C(O)N(R⁵)R⁶ where:

R⁵ and R⁶ are each independently hydrogen or alkyl;

R⁷ is hydrogen or alkyl; and

R¹⁰ and R¹¹ are independently hydrogen or alkyl.

Of this class of compounds, preferred compounds are selected from thegroup consisting of:

N-(4-chlorophenyl)-2-[((3-chloro-5-carboxythiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;and

N-(4-chlorophenyl)-2-[((3-chloro-4-(hydroxymethyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.

Of the subgroup of compounds described above, another preferred class ofcompounds are those compounds wherein:

R³ is a radical of formula (i): ##STR30## where:

r is 1 or 2;

R¹³ is alkyl, halo or --OR⁵ (where R⁵ is alkyl), and

each R¹⁴ is independently hydrogen, halo, --C(R⁷)H--N.sup.⊕ (R⁹)(R¹⁶)₂,--S(O)_(p) --R¹⁵, --C(R⁷)H--N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to6), --C(R⁷)H--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --C(R⁷)H--O--R⁸--CH(OH)--CH₂ --OR⁵, or --C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t) --CH₂ --OR⁵(where t is 1 to 6) where:

R⁵ and R⁶ are independently hydrogen or alkyl;

R⁷ is hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene chain;

R¹⁰ and R¹¹ are independently hydrogen, alkyl or --R⁸ --OR⁵ where R⁸ isa straight or branched alkylene chain and R⁵ is hydrogen or alkyl; and

R¹⁵ is alkyl or --N(R⁵)R⁶ ; and

each R¹⁶ is independently alkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁸--N(R⁵)R⁶, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), or

both R¹⁶ 's together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)R⁵,--C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸ --O)_(t) --R⁵(where t is 1 to 6).

Of this class of compounds, preferred compounds are selected from thegroup consisting of:

N-(4-chlorophenyl)-2-[((3-chloro-4-((N',N'-dimethyl-N'-(2-hydroxyethyl)ammonio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((((2-hydroxyethoxy)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((2-(2-methoxyethoxy)ethoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)methyI)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((2-methoxyethoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N',N'-dimethyl-N'-(3-hydroxypropyl)ammonio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2,3-dihydroxypropyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2,3,4,5,6-pentahydroxyhexyl)amino)methyl)thiophen-2-yl)carbonylamino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2-(hydroxyethoxy)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-(methylsulfonyl)thiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chlorothiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-bromothiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chloro4-((1-methylethyl)sulfonyl)thiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((4-(methylamino)sulfonyl-3-methylthiophen-2-yl)carbonyl)amino]-5-methylbenzamide;and

N-(4-chlorophenyl)-2-[((3-methoxythiophen-2-yl)carbonyl)amino]-5-methylbenzamide.

Of the compounds of formula (I) described above, another preferred groupof compounds are those compounds of formula (I) wherein:

A is --CH-- or ═N--;

m is 1 to 3;

n is 1 to 4;

D is --N(H)--C(O)-- or --N(H)--CH₂ --;

E is --C(O)--N(H)--; (where the nitrogen atom is bonded to the aromaticring containing the R⁴ substituent);

each R¹ is independently hydrogen, alkyl, aryl, aralkyl, halo,haloalkyl, cyano, --OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵,--C(O)N(R⁵)R⁶, --N(R⁵)R⁶, --O--C(O)R⁵, or --N(R⁵)--CH(R¹²)--C(O)OR⁵ ;

R² is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, --OR⁵,--S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵, --OC(O)--R⁵,--C(O)N(R⁵)R⁶, --N(R¹⁰)R¹¹, --C(R⁷)H--OR⁵, --C(R⁷)H--S(O)_(p) --R⁹(where p is 0 to 2), --O--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--C(R⁷)H--N(R⁵)R⁶, --O--R⁸ --CH(OH)--CH₂ --N(R¹⁰)R¹¹ --O--R⁸--N(R¹⁰)R¹¹, --O--R⁸ --O--C(O)R⁵, --O--R⁸ --CH(OH)--CH₂ --OR⁵ ; --O--(R⁸--O)_(t) --R⁵ (where t is 1 to 6), --O--R⁸ --C(O)R⁵, --O--R⁸ --C(O)OR⁵,--N(R⁵)--R⁸ --N(R¹⁰)R¹¹, --S(O)_(p) R⁸ --N(R⁵)R⁶ (where p is 0 to 2),--S(O)_(p) --R⁸ --C(O)OR⁵ (where p is 0 to 2), or--N(R⁵)--CH(R¹²)--C(O)OR⁵ ;

R³ is a radical of formula (ii): ##STR31## where v is 1 to 4;

R¹³ is hydrogen, alkyl, halo, haloalkyl, --N(R⁵)R⁶, --C(R⁷)H--N(R⁵)R⁶,--OR⁵, --S(O)_(p) --R⁸ --N(R⁵)R⁶ (where p is 0 to 2) orheterocyclylalkyl (where the heterocyclic ring is optionally substitutedby one or more substituents selected from the group consisting of alkyl,halo, aralkyl, nitro and cyano); and

each R¹⁴ is independently hydrogen, alkyl, halo, formyl, acetyl,--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--N.sup.⊕ (R⁹)(R¹⁶)₂,--N(R⁵)--R⁸ --C(O)OR⁵, --C(R⁷)H--N(R⁵)--R⁸ --C(O)OR⁵, --C(O)OR⁵, --OR⁵,--C(R⁷)H--OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --C(R⁷)H--S(O)_(p)--R¹⁵ (where p is 0 to 2), --S(O)_(p) --N(R⁵)R⁶ (where p is 0 to 2),--C(O)N(R⁵)R⁶, --C(R⁷)H--N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --O--R⁸--CH(OH)--CH₂ --OR⁵, --C(R⁷)H--O--R⁸ --CH(OH)--CH₂ --OR⁵,--C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t) --CH₂ --OR⁵ (where t is 1 to 6),--C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹, or --C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰;

each R⁴ is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro,--OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, or --R⁸ --N(R⁵)R⁶ ;

R⁵ and R⁶ are each independently hydrogen, alky, aryl or aralkyl;

each R⁷ is independently hydrogen or alkyl;

each R⁸ is independently a straight or branched alkylene or alkylidenechain;

each R⁹ is independently alkyl, aryl or aralkyl;

R¹⁰ and R¹¹ are each independently hydrogen, alkyl, aryl, aralkyl,formyl, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸--N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂,--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, cycloalkyl (optionally substitutedby one or more substituents selected from the group consisting of alkyl,halo and --OR⁵), heterocyclyl (optionally substituted by alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and--C(O)N(R⁵)R⁶);

or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, oxo, ═N(R¹⁷), --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁵, --R⁸--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t) R⁵ (where t is 1 to 6), and--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6);

R¹² is a side chain of an α-amino acid;

R¹⁵ is alkyl, haloalkyl, aryl, aralkyl, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸--N(R⁵)R⁶, --R⁸ --C(O)OR⁵ heterocyclyl (optionally substituted by one ormore substituents selected from the group consisting of alky, aryl,aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶);

or R⁵ and R¹⁵ together with the nitrogen to which they are attached forma N-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl; and

each R¹⁶ is independently alkyl, aryl, aralkyl, --R⁸ --OR⁵,--R--N(R⁵)R⁶, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), or

both R¹⁶ 's together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)R⁵,--C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸ --O)_(t) --R⁵(where t is 1 to 6); and

each R is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶.

Of this group of compounds, preferred compounds are selected from thegroup consisting of:

N-phenyl-2-[((3-chicrobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(pyridin-3-yl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(pyridin-2-yl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-methoxyphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(3-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-bromophenyl)-2-[((3-chlorobenzor[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(5-chloropyridin-2-yl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(3-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(3-methylphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chloro-2-methylphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-cyanophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-fluorophenyl)-2-[((benzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-fluorophenyl)-2-[((3-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-methoxybenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]benzamide;

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methoxybenzamide;

N-(4-bromophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-chlorbenzamide;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methylbenzamide;

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(pyrrolidin-1-yl)methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-(trifuoromethyl)benzamide;

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(dimethylamino)methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(4-methylpiperazin-1-yl)benzamide;

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(amino)methylbenzamide;

N-(4-chlorophenlyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-hydroxybenzamide;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dimethoxybenzamide;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dihydroxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-ylcarbonyl)amino]-5-fluorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-chlorobenzamide;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxybenzamide;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-hydroxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-fluorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-6-fluorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-hydroxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dihydroxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyt)amino]-4,5-dimethoxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]benzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-aminobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-methyl-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methyl-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-fluoro-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-difiuorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-(N'-methyl-N'-(3-(dimethylamino)propylamino-5-fluorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-(4-methylpiperazin-1-yl)-5-fluorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-((3-(4-methylpiperazin-1-yl)propyl)amino)-5-fluorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-6-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-(dimethylamino)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-6-(dimethylamino)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-(4-methylpiperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-6-(4-methylpiperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-6-(4-(carboxymethyl)piperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-6-((methoxycarbonyl)methylthio)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-ylcarbonyl)amino]-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-chloro-5-(N'-methyl-N'-(ethoxycarbonyl)methylamino)benzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(N'-methyl-N'-(2-(dimethylamino)ethyl)amino)-3-chlorothiophen-2-yl)carbonyl)amino]-3-chloro-5-(N'-methyl-N'-(ethoxycarbonyl)methylamino)benzamide;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-hdyroxy-4-((1,1-dimethylethyl)carbonyl)oxybenzamide;and

N'-(4-chlorophenyl)-2-((3-methylbenzo[b]thien-2yl)methyl)amino-5-benzamide.

Of the compounds disclosed above, the following compounds are the mostpreferred compounds of the invention:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide,

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide,

N-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,

N-(5-chloropyddin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(S)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,

N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(imidazolin-2-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(pyridin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;and

N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

Preparation of Compounds of The Invention

It is understood that in the following description, combinations ofsubstituents and/or variables on the depicted formulae are permissibleonly if such combinations result in stable compounds.

For purposes of illustration only and unless otherwise indicated, thefollowing Reaction Schemes are directed to the preparation of thecompounds of the invention as set forth above in the Summary of theInvention as compounds of formula (I). In particular, for purposes ofillustration only and unless otherwise indicated, the compounds preparedin the following Reaction Schemes are compounds of formula (I) wherein Dis --N(R⁵)--C(O)-- (where the nitrogen is bonded to the phenyl ringhaving the R¹ and R² substituents), and E is --C(O)--N(R⁵)-- (where thenitrogen is bonded at the 2-position of the pyridinyl (if A is ═N--) orto the phenyl (if A is ═CH--) having the R⁴ substituent) and R³ is aradical of the formula (i): ##STR32##

where each R¹³ and each R¹⁴ are as described in each following ReactionScheme. It is understood that the other compounds of the invention maybe prepared by similar methods as described herein.

A. Preparation of Compounds of Formula (Ia)

Compounds of formula (Ia) are compounds of the invention wherein R¹³ ischloro and the R¹⁴ substituent is in the 4-position of the thienylradical. These compounds are prepared as described below in ReactionScheme 1 where A is ═CH-- or ═N--, each R^(1a) is independentlyhydrogen, alkyl, aryl, aralkyl, halo, cyano, --OR⁵, --S(O)_(p) --R⁹(where p is 0 to 2), --C(O)OR⁵, --O--C(O)--R⁵, --C(O)N(R⁵)R⁶, --N(R⁵)R⁶; R^(2a) is hydrogen, alkyl, aryl, aralkyl, halo, cyano, --OR⁵,--S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵, --C(O)N(R⁵)R⁶,--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸ --N(R¹⁰)R¹¹,--C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--S(O)_(p) --R⁹ (where p is 0to 2), --C(R⁷)H--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --O--R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --C(R⁷)H--N(R⁵)R⁶, --C(R⁷)H--R⁸--N(R⁵)R⁶, --O--R⁸ --CH(OH)--CH₂ --N(R¹⁰)R¹¹, --O--R⁸ --N(R¹⁰)R¹¹,--O--R⁸ --O--C(O)R⁵, --O--R⁸ --CH(OH)--CH₂ --OR⁵, --O--(R⁸ --O)_(t) R⁵(where t is 1 to 6), --O--(R⁸ --O)_(t) --R¹⁹ (where t is 1 to 6),--O--R⁸ --C(O)R⁵, --O--R⁸ --C(O)R¹⁹, --O--R⁸ --C(O)OR⁵, --N(R⁵)--R⁸--N(R¹⁰)R¹¹, --S(O)_(p) --R⁸ --N(R⁵)R⁶ (where p is 0 to 2), or--S(O)_(p) --R⁸ --C(O)OR⁵ (where p is 0 to 2); each R⁴ is independentlyhydrogen, alkyl, halo, cyano, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶,--C(O)N(R⁵)R⁶, or --R⁸ --N(R⁵)R⁶ ; each R⁵ and R⁶ is as described abovein the Summary of the Invention for compounds of formula (I); R^(5a) ishydrogen; R⁷ is hydrogen or alkyl; each R⁸ and R⁹ are as described abovein the Summary of the Invention for compounds of formula (I); each R¹⁰and R¹¹ is independently hydrogen, alkyl, aryl, aralkyl, formyl, cyano,--R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸--S(O)_(p) --R¹⁵ (where p is 0 to 2), --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸ --C(O)NH₂, --C(S)NH₂,--C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸ --C(O)--N(R⁵)R¹⁵,--C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸ --N(R⁵)--C(O)R¹⁵,--C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, --R⁸ --N(R⁵)--P(O)(OR⁵)₂,cycloalkyl (optionally substituted by one or more substituents selectedfrom the group consisting of alkyl, halo and --OR⁵), heterocyclyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, aryl, aralkyl, halo, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵,--S(O)_(p) R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to2), --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); or R¹⁰ and R¹¹ together with thenitrogen to which they are attached form a N--heterocyclic ringcontaining zero to three additional hetero atoms, where the heterocylicring is optionally substituted by one or more substituents selected fromthe group consisting of alkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸--CN, ═N(R¹⁷), --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸--N(R⁵)R⁶, --C(O)N(R⁵)R⁶, --R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶,--C(O)R⁵, --C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --S(O)_(p) --R⁹(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸--O)_(t) --R⁵ (where t is 1 to 6), and heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶,and --C(O)N(R⁵)R⁶); R^(14a) is cyano, --N(R¹⁰)R¹¹, --N.sup.⊕ (R⁹)(R¹⁶)₂,--N(R⁵)--R⁸ --C(O)OR⁵, --S--R¹⁵, --S--R⁸ --C(O)OR⁵, --S--R⁸ --N(R⁵)R⁶,--N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --N(R⁵)--R⁸--[CH(OH)]_(t) --CH₂ --OR⁵ (where t is 1 to 6), --S--R⁸ --OR¹⁵ ; orR^(14a) is heterocyclyl wherein the heterocyclic ring is optionallysubstituted by alkyl, aryl, aralkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or--C(O)N(R⁵)R⁶ ; where each R¹⁵ and R¹⁶ are as described above in theSummary of the Invention for compounds of formula (I) except thatneither can be or contain haloalkyl; R¹⁷ is as described in the Summaryof the Invention for compounds of formula (I); and X is chloro or bromo:##STR33##

Compounds of formula (A), formula (C), and formula (H) are commerciallyavailable, for example, from Aldrich Co. Compounds of formula (F) arecommercially available or may be prepared according to methods describedherein.

In general, compounds of formula (Ia) are prepared by first reacting acompound of formula (A) in an aprotic solvent, for example, methylenechloride, at temperatures of between about -10° C. to about 10° C.,preferably at 0° C., with a halogenating agent, for example, oxalylchloride. The reaction mixture is allowed to warm to ambient temperatureand stirred for about 8 to 20 hours, preferably for about 16 hours, toproduce a compound of formula (B), which is isolated from the reactionmixture by standard techniques (such as removal of solvents).

The compound of formula (B) in an aprotic solvent, for example,methylene chloride, at temperatures of between about -10° C. to about10° C., preferably at 0° C., is then treated with a compound of formula(C) in the presence of a base, for example, triethylamine. The reactionmixture is then stirred for about 20 to 30 minutes, preferably for about20 minutes, at temperatures of between about --10C to about 10IC,preferably at 0° C, then warmed to ambient temperature, and stirred forabout 1 to about 20 hours, preferably for about 16 hours. The compoundof formula (D) is then isolated from the reaction mixture by standardisolation techniques, such as evaporation of solvents, extraction andconcentration.

The compound of formula (D) is then reduced by treatment with a reducingagent, such as tin(II) chloride under standard reducing conditions toproduce a compound of formula (E), which is isolated from the reactionmixture by standard techniques.

The compound of formula (E) in an aprotic solvent, for example,methylene chloride, at temperatures of between about -10° C. to about100° C., preferably at 0° C., is then treated with a compound of formula(F) in the presence of a base, for example, pyridine. The compound offormula (G) is then isolated from the reaction mixture by standardisolation techniques, such as concentration and trituration with water.

The compound of formula (G) in an aprotic solvent, such as DMF, attemperatures of between about -10° C. to about 10° C., preferably at 0°C., is then treated with a compound of formula (H). The reaction mixtureis stirred for about 20 minutes to an hour, preferably for about 30minutes, and then allowed to warm to ambient temperature. After stirringfor about 6 to about 20 hours, preferably for about 7 hours, thecompound of formula (Ia) is isolated from the reaction mixture bystandard isolation techniques, such as filtration and purification byflash chromatography.

The compound of formula (H) may be present as an acid salt, wherein thecorresponding free base is formed in situ by the addition of a base tothe reaction mixture, or is treated with a base prior to the reactionwith the compounds of formula (G) to form the free base.

Any unprotected amino substituent must be protected prior to Step 4 toavoid acylation. Any carboxy substituent must also be esterified priorto Step 1. The resulting compounds may be deprotected when needed byappropriate methods known to those skilled in the art to affordcompounds having an unsubstituted amino or carboxy subsfituent thereon.

Compounds of the invention where D is --N(R⁵)--S(O)_(p) -- (where p is2) may be prepared by methods disclosed above by reacting a compound offormula (E) with the sulfonyl chloride of the substituted thiophene orbenzothiophene radical.

Compounds of the invention where E is --N(R⁵)--(O)_(p) -- (where p is2), can be formed by reacting a substituted benzene sulfonyl chloridewith a compound of formula (C) and then proceeding with Steps 3-5 above.

Compounds of formula (E) where R^(5a) is hydrogen may be reacted with anappropriate alkylating agent prior to Step 4 to produce compounds whereR^(5a) is alkyl, aryl or aralkyl.

Compounds of the invention where R¹³ is --S(O)_(p) --R⁸ --N(R⁵)R⁶ (wherep is 0) may be prepared from the corresponding halo as described herein.Compounds where R¹³ is heterocyclylalkyl may be made from substitutionfrom the corresponding haloalkyl.

Compounds of formula (G) may be reacted with tertiary amines of theformula N(R⁹)(R¹⁶)₂ where R⁹ and R¹⁶ are as described above in theSummary of the Invention for compounds of formula (I) by methods similarto those described above to prepare compounds of the invention

wherein R^(4a) is --N.sup.⊕ (R⁹)(R¹⁶)₂.

Any unoxidized sulfur and nitrogen may be oxidized after the final stepin Reaction Scheme 1 by methods known to those skilled in the art toproduce the desired oxidized substituents.

Compounds of formula (Ia) where R^(14a) contains a --N(H)R¹⁰ group maybe reacted with a heterocyclic compound having a reactive halogen toform compounds where R^(14a) contains a --N(R¹⁰)R¹¹ group wherein R¹¹ isheterocyclyl.

Compounds of formula (Ia) where R^(14a) contains a secondary aminosubstituent may be reacted with an aldehyde in an aprotic solvent, suchas acetonitrile, in the presence of a reducing agent such as sodiumcyanoborohydride to form compounds wherein the amino substituent isfurther substituted by an alkyl or aralkyl group.

Compounds of formula (Ia) where R^(14a) is --N(R¹⁰)R¹¹ where R¹⁰ ishydrogen and R¹¹ is --R⁸ --OR⁵ (where R⁵ is hydrogen and R⁸ is ethyl orpropyl optionally substituted by alkyl or alkoxyalkyl) can be reactedwith cyanogen bromide to form compounds of the invention where R¹⁴ is--C(R⁷)H--N(R¹⁰)R¹¹ where R¹⁰ and R¹¹ together with the nitrogen towhich they are attached form optionally substituted2-iminooxazolidin-3-yl or optionally substitutedtetrahydro-2-amino-1,3-oxazinyl.

Compounds of formula (Ia) where R^(14a) is --N(R¹⁰)R¹¹ where R¹¹ ishydrogen and R¹⁰ is alkyl, aryl or aralkyl can be reacted with a cyanohalide under basic conditions to form compounds of the invention whereR¹⁴ is --C(R⁷)H--N(R¹⁰)--CN, which can then be reacted with an azide inthe presence of tributyl tin chloride in an aprotic solvent to form acompound of the invention where R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where R¹¹ istetrazolyl attached to the nitrogen through a carbon atom in theheterocyclic ring.

Compounds of formula (G) may be treated with an oxidizing agent to formthe corresponding N-oxide when A is ═N--, and then treated withcompounds of formula (H) to form other compounds of the invention wherethe pyridinyl ring is oxidized.

Compounds of formula (Ia) where R^(14a) is --N(R¹⁰)R¹¹ where R¹⁰ ishydrogen and R¹¹ is --R⁸ --N(R⁵)R⁶ where R⁸ is ethyl or propyl and atleast one R⁵ or R⁶ is hydrogen may be further treated with an orthoester under mild acidic conditions to form compounds of the inventionwhere R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where R¹⁰ and R¹¹ together with thenitrogen form an optionally substituted imidazolinyl. Other compounds ofthe invention may be similarly made. Such compounds wherein theimidazolinyl is substituted with an appropriate haloalkyl may be furthertreated with a compound of formula (H) in an aprouic solvent to formcompounds wherein the imidazolinyl is substituted by the correspondingR^(14a) group.

Compounds of formula (Ia) where R^(14a) is --N(R¹⁰)R¹¹ where R¹⁰ and R¹¹together with the nitrogen form a 2-aminoimidazolyl in a protic solventof the formula R⁵ --OH may be further treated with a halogenating agent,such as N-chlorosuccinimide (NCS) in the presence of a strong acid toform compounds of the invention where R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ whereR¹⁰ and R¹¹ form a 2-iminoimidazolidinyl substituted at the 4- and5-position with --OR⁵. Other compounds of the invention may be similarlymade.

Compounds of formula (Ia) where R^(14a) is --N(R¹⁰)R¹¹ where R¹⁰ ishydrogen and R¹¹ is --R⁸ --N(R⁵)R⁶ where either R⁵ or R⁶ is hydrogen maybe further treated with phosphoryl chloride in the presence of a base,followed by treatment with a compound of the formula R⁵ --OH to formcompounds of the invention where R¹⁴ is --C(R⁷)H--N(R⁵)--P(O)(OR⁵)₂.

Compounds of formula (Ia) where R^(14a) is --N(R¹⁰)R¹¹ where R¹⁰ and R¹¹together with the nitrogen form 2-methylthioimidazolinyl may be furthertreated with N(R⁵)H--R⁸ --OR⁵ or with NH₂ --R⁸ --C(O)--N(R⁵)R⁶ to formcompounds of the invention where R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where R¹⁰and R¹¹ together with the nitrogen form a imidazolinyl substituted atthe 2-position with --N(R⁵)--R⁸ --OR⁵ or with ═NR¹⁷ where R¹⁷ is --R⁸--C(O)--N(R⁵)R⁶, respectively.

Compounds of formula (Ia) where R^(14a) is --N(R¹⁰)R¹¹ where R¹⁰ and R¹¹together with the nitrogen form a N-heterocyclic substituted with formylmay be treated under standard reducing conditions to form compounds ofthe invention where R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where R¹⁰ and R¹¹together with the nitrogen form a N-heterocyclic substituted withhydroxymethyl. Other compounds of the invention may be similarly made.

Compounds of formula (Ia) where R^(14a) is --N(R¹⁰)R¹¹ where R¹⁰ isalkyl and R¹¹ is oxazolin-2-yl may be treated with compounds of theformula R⁵ --C(O)OH to form compounds of the invention where R¹⁴ is--N(R¹⁰)R¹¹ where R¹⁰ is alkyl and R¹¹ is --C(O)--N(R⁵)R¹⁵ where R⁵ ishydrogen and R¹⁵ is --R⁸ --O--C(O)R⁵ where R⁸ is ethyl.

Other compounds of formula (Ia) may be prepared according to the methodsdescribed herein according to methods known to those skilled in the art.

B. Preparation of Compounds of Formula (Ib)

Compounds of formula (Ib) are compounds of the invention and areprepared as follows in Reaction Scheme 2 wherein A is ═CH-- or ═N--,each R^(1a) is as defined in Reaction Scheme 1 above; R^(2a) is asdefined in Reaction Scheme 1 above; R⁵ is as defined in the Summary ofthe Invention for compounds of formula (I); R^(5a) is hydrogen; each R⁴and R¹³ is as defined in the Summary of the Invention for compounds offormula (I), R¹⁴ is as described above in the Summary of the Inventionfor compounds of formula (I); and X is chloro or bromo: ##STR34##

Compounds of formula (E) are prepared above in Reaction Scheme 1.Compounds of formula (J) are commercially available, e.g., fromLancaster, or may be prepared by methods known to those skilled in theart from compounds of formula (J) where X is --OCH₃ (and where R¹³ orR¹⁴ do not contain a hydrolyzable group such as an ester), which ishydrolyzed to the acid and then converted to the acid chloride to form acompound of formula (J). In addition, compounds of formula (J) may beprepared according to methods disclosed herein.

In general, compounds of formula (lb) are prepared by treating acompound of formula (E) with a compound of formula (J) in the presenceof a base, preferably pyridine, at temperatures of between about -10° C.to about 10° C., preferably at 0° C. The reaction mixture is allowed towarm to ambient temperature and then stirred for about 8 to 20 hours,preferably for about 16 hours. The compound of formula (Ib) is thenisolated from the reaction mixture by standard isolation techniques,such as filtration and recrystallization.

Compounds of formula (Ib) where R¹⁴ is hydrogen, halo, formyl, acetyl,--N(R¹⁰)R¹¹, --N(R⁵)--R⁸ --C(O)OR⁵, --C(O)OR⁵, --OR⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --S(O)_(p) --N(R⁵)R⁶, or --C(O)N(R⁵)R⁶ ; andR^(1a), R^(2a) or R¹³ is alkyl, may be treated under standardhalogenating conditions to form compounds where R^(1a), R^(2a) or R¹³ ishaloalkyl. The resulting compounds may then be treated with HN(R¹⁰)R¹¹or HN(R⁵)R⁶ to form compounds where R^(1a), R^(2a) or R¹³ is--C(R⁷)H--N(R¹⁰)R¹¹ or --C(R⁷)H--N(R⁵)R⁶.

Compounds of formula (Ib) where R¹⁴ is cyano may be treated withmethanol or ethanol to form the corresponding imidate, which can then betreated with a compound of formula NH₂ --R⁸ -- N(R⁵)R⁶ where at leastone R⁵ or R⁶ is hydrogen to form compounds of the invention where R¹⁴ isheterocyclyl containing at least two nitrogen atoms. Alternatively, theimidate so formed can be treated with a compound of formula N(H)(R⁵)R⁶to form compounds of the invention where R¹⁴ is --C(NH)--N(R⁵)R⁶ whichcan be further treated under conditions similar to those describedherein to form compounds of the invention where R¹⁴ is--C(NR¹⁷)--N(R⁵)R⁶ where R¹⁷ is as described above in the Summary of theInvention for compounds of formula (I).

Compounds of formula (Ib) where one or more R^(1a) 's is hydroxy and R²is hydrogen may be further treated with a compound of formula R⁵--C(O)--X where X is chloro or bromo to produce compounds of theinvention where one or more R^(1a) 's is --O--C(O)--R⁵.

Compounds of formula (Ib) where R¹⁴ is --N(R¹⁰)R¹¹ where at least oneR¹⁰ or R¹¹ is hydrogen can be treated with the appropriate X--C(O)--R¹⁵where X is bromo or chloro and R¹⁵ is as described above in the Summaryof the Invention for compounds of formula (I) to form compounds of theinvention where R¹⁴ is --N(R¹⁰)(R¹¹) where R¹⁰ is hydrogen, alkyl, arylor aralkyl and R¹¹ is --C(O)--R¹⁵. During this process, othersubstitutents of compounds of formula (Ib) which contain a reactivehydroxy, amino or carboxy group may also be acylated.

C. Preparation of Compounds of Formula (Ic)

Compounds of formula (Ic) are compounds of the invention. They areprepared from compounds of formula (Ib) where A is ═CH-- or ═N--,R^(14b) is --CH₂ --R⁷ where R⁷ is hydrogen or alkyl as illustrated belowin Reaction Scheme 3 wherein each R^(1a), R^(2a), R⁴, R⁵, R^(5a) andR^(14a) are as defined above in Reaction Scheme 1, and R¹³ is as definedabove in the Summary of the Invention for compounds of formula (I), andX is bromo and chloro: ##STR35##

Compounds of formula (Ib) are prepared herein. Compounds of formula (H)are commercially available or may be prepared according to methods knownto those skilled in the art or by methods disclosed herein.

In general, compounds of formula (Ic) are prepared by first treating acompound of formula (Ib) in an organic solvent, such as benzene, with anhalogenating agent under conditions to form the halide radical (such asirradiation). The compound of formula (K) is then isolated from thereaction mixture by standard techniques, such as concentration andtrituration with solvent.

The compound of formula (K) in an aprotic solvent, such as methylenechloride, is treated with a compound of formula (H). The reactionmixture is stirred at ambient temperature for about 8 to about 20 hours,preferably for about 18 hours. The compound of formula (Ic) is thenisolated from the reaction mixture by standard isolation techniques,such as extraction, concentration and purification by HPLC.

Compounds of the invention where R¹³ is haloalkyl may be prepared byhalogenating the corresponding alkyl substituent according to methodsknown to those skilled in the art. The compounds so formed can then betreated with the appropriate HN(R⁵)R⁶ group under conditions similar tothose described above for preparing compounds of formula (Ic) to producecompounds of the invention where R¹³ is --C(R⁷)H--N(R⁵)R⁶.

For better yield in the above Reaction Scheme, it is recommended thatR^(1a), R^(2a), R⁴, and R¹³ do not contain an alkyl group, since thisalkyl will also be halogenated and will subsequently react with compoundof formula (H) during the reaction.

Compounds of formula (K) where X is bromo may be treated under standardsubstitution conditions to form compounds of formula (Ic) where R^(14a)is hydroxy. These compounds may be further oxidized under standardoxidizing conditions to form compounds of the invention where R¹⁴ isformyl, which can further oxidized to form compounds of the inventionwhere R¹⁴ is --C(O)OR⁵.

D. Preparation of Compounds of Formula (Id)

Compounds of formula (Id) are compounds of the invention where R¹³ ischloro. They are prepared from compounds of formula (M) which arecompounds of either formula (G) or (K) as illustrated below in ReactionScheme 4 where A is ═CH-- or ═N--, each R^(1a), R^(2a), each R⁴, R⁵,R^(5a) and R⁷ are as defined above in Reaction Scheme 1; R^(14c) is--OR⁵, --S--R¹⁵, --S--R⁸ --C(O)OR⁵, --S--R⁸ --N(R⁵)R⁶, --O--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), --S--R⁸ --OR⁵, --CN or --N(R¹⁰)R¹¹ (where R¹⁰and R¹¹ together with the nitrogen to which they are attached form a aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸ --CN, ═N(R^(17a)),--OR^(5b), --C(O)OR^(5b), --R⁸ --C(O)OR^(5b), --N(R^(5b))R^(6b), --R⁸--N(R^(5b))R^(6b), --C(O)N(R^(5b))R^(6b), --R⁸ --C(O)N(R^(5b))R^(6b),--N(R^(5b))--N(R^(5b))R^(6b), --C(O)R^(5b), --C(O)--(R⁸ --O)_(t)--R^(5b) (where t is 1 to 6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸ --O)_(t) --R^(5b) (where t is1 to 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR^(5b), --C(O)OR^(5b), --N(R⁵)R^(6b), and--C(O)N(R^(5b))R^(6b)) where R^(5b) and R^(6b) are alkyl, aryl oraralkyl and R^(17a) is as defined for R¹⁷ in the Summary of theInvention for compounds of formula (I) except R^(17a) can not behydrogen; and where each R⁸, R⁹ and R¹⁵ are as defined above in theSummary of the Invention for compounds of formula (I); and Y is a metalcation: ##STR36##

Compounds of formula (N) are commercially available or may be preparedaccording to methods known to those skilled in the art.

In general, the compounds of formula (Id) are prepared by reacting acompound of formula (M) in an aprotic solvent with a compound of formula(N). The reaction mixture is stirred at ambient temperature for about 8to about 20 hours, preferably for about 16 hours. The compound offormula (Id) is then isolated from the reaction mixture by standardisolation techniques, such as extraction, concentration of product, andflash chromatography.

Alternatively, a compound of formula HR^(14c) in an aprotic solvent,such as DMF, is treated with a strong base, such as sodium hydride, atambient temperature to form the corresponding salt. The compound offormula (M) in an aprotic solvent, such as DMF, is then added to thereaction mixture containing the salt. The reaction mixture is stirred atambient temperature for about 10 to 20 hours, preferably for about 18hours. The compound of formula (Id) is then isolated from the reactionmixture by standard isolation techniques, such as extraction,concentration and flash chromatography.

In general, this reaction scheme is used for those amines, alcohols andmercapto compounds of formula HR^(14c) which are not reactive enough tobe used in Reaction Schemes 1 or 2 above. The salt can be formed in situor can be isolated.

Compounds of formula (Ia) where R^(14c) is cyano may be further treatedwith hydroxylamine under basic conditions in a protic solvent to formcompounds of the invention where R¹⁴ is --C(R⁷)H--C(NR¹⁷)--R¹⁰ where R¹⁷is --OH.

E. Preparation of Compounds of Formula (If)

Compounds of formula (If) are compounds of the invention wherein a R¹⁴substituent is --C(R⁷)H--N(R¹⁰)R¹¹ where R⁷ is hydrogen or alkyl, R¹⁰ ishydrogen, alkyl, aryl, aralkyl, --OR⁵ (where R⁵ is not hydrogen), --R⁸--OR⁵ (where R⁵ is not hydrogen), --R⁸ --N(R⁵)R⁶, cycloalkyl (optionallysubstituted as described above in the Summary of the Invention forcompounds of formula (I) except that R⁵ can not be hydrogen), andheterocyclylalkyl (optionally substituted as described above in theSummary of the Invention for compounds of formula (I) except that R⁵ cannot be hydrogen), and R¹¹ is --S(O)₂ --R^(15a) where R^(15a) is alkyl,haloalkyl, aryl, aralkyl, --R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --R⁸--N(R⁵)R⁶, --R⁸ --C(O)OR⁵, heterocyclyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR^(5b), --R--OR^(5b), --C(O)OR^(5b),--N(R^(5b))R^(6b) and --C(O)N(R^(5b))R^(6b) where each R^(5b) and R^(6b)is alkyl, aryl or aralkyl), or heterocyclylalkyl (optionally substitutedby one or more substituents selected from the group consisting of alkyl,aryl, aralkyl, halo, haloalkyl, --OR^(5b), --R⁸ --OR^(5b),--C(O)OR^(5b), --N(R^(5b))R^(6b) or --C(O)N(R^(5b))R^(6b) where eachR^(5b) or R^(6b) is alkyl, aryl or aralkyl). They are prepared fromcompounds of formula (M) as illustrated below in Reaction Scheme 5 whereA is ═CH-- or ═N--; R^(1a), R^(2a), R⁴, R⁵ and R^(5a) are as describedabove in Reaction Scheme 1; R¹⁰ and R^(15a) are as described above; andX is chloro or bromo: ##STR37##

Compounds of formula (O) are commercially available or may be preparedaccording to methods known to those of ordinary skill in the art. Thecompound of formula (Ie) is a compound of formula (Ia) where R^(14a) is--N(R¹⁰)R¹¹ and is prepared herein.

In general, compounds of formula (If) are prepared by treating acompound of formula (Ie) in the presence of base, such as pyridine, attemperatures of between about -10° C. to about 10° C., preferably at 0°C., with a compound of formula (O). The reaction mixture is allowed towarm to ambient temperature and then stirred for about 8 to about 20hours, preferably for about 16 hours. The compound of formula (If) isthen isolated from the reaction mixture by standard isolationtechniques, such as removal of solvents in vacuo and purification byflash chromatography.

This reaction scheme can also be used with compounds of the formulaX--S(O)₂ --N(R¹⁰)R¹¹ to make compounds of the invention where R¹⁴ is--C(R⁷)H--N(R¹⁰)--S(O)₂ --N(R¹⁰)R¹¹.

F. Preparation of Compounds of Formula (Ig)

Compounds of formula (Ig) are compounds of the invention wherein a R¹⁴is --C(R⁷)H--N(R¹⁰)R¹¹ where R⁷ is hydrogen or alkyl, R¹⁰ is hydrogen,alkyl, aryl, aralkyl, --OR⁵ (where R⁵ is not hydrogen), --R⁸ --OR⁵, --R⁸--N(R⁵)R⁶, cycloalkyl (optionally substituted as described above in theSummary of the Invention for compounds of formula (I) except that R⁵ cannot be hydrogen), and heterocyclylalkyl (optionally substituted asdescribed above in the Summary of the Invention for compounds of formula(I) except that R⁵ can not be hydrogen); and R¹¹ is either--C(O)--N(R⁵)R^(15b) or --C(S)--N(R⁵)R^(15b) where each R⁵ is hydrogenand each R^(15b) is hydrogen, alkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁸--C(O)OR⁵ or heterocyclylalkyl (optionally substituted by alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶).They are prepared as described below in Reaction Scheme 6 wherein A is═CH-- or ═N--; R^(1a), R^(2a), R⁴, R⁵, and R^(5a) are as described abovein Reaction Scheme 1; and R^(15b) is as described above; and Z is eitheroxygen or sulfur: ##STR38##

Compounds of formula (P) are commercially available, or may be preparedaccording to methods known to those skilled in the art. The compounds offormula (Ie) are compounds of formula (Ia) where R^(14a) is --N(R¹⁰)R¹¹and are prepared by methods disclosed herein.

In general, compounds of formula (Ig) are prepared by treating acompound of formula (Ie) in an aprotic solvent, such as dioxane, with acompound of formula (P). The reaction mixture is stirred at ambienttemperature for about 8 to about 20 hours, preferably for about 16hours. The compound of formula (Ig) is isolated from the reactionmixture by standard isolation techniques, such as concentration ofproduct and purification by flash chromatography.

Alternatively, to produce compounds of formula (Ig) where R^(15b) ishydrogen, compounds of formula (Ie) may be reacted with potassiumisocyanate (K--N═C═O). Alternatively, compounds of formula (Ie) may bereacted first with phosgene or equivalent, followed by reacting theresulting product with a disubstituted amine or a cyclic amine to formcompounds of the invention where R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where R¹⁰ isas described above for the compounds of formula (Ig) and R¹¹ is--C(O)--N(R⁵)R¹⁵ where R⁵ and R¹⁵ are independently alkyl, aryl oraralkyl, or R⁵ and R¹⁵ together with the nitrogen to which they areattached form a N-heterocyclic ring as defined in the Summary of theInvention for compounds of formula (I).

Compounds of formula (Ig) where R^(15b) is hydrogen can be furtherreacted with a halocetaldehyde dialkylacetal in the presence of a proticsolvent, preferably an alkanol, to form compounds of the invention whereR¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where R⁷ is hydrogen or alkyl, and R¹⁰ is asdescribed above for the Reaction Scheme and R¹¹ is an oxazol-2-ylsubstituent.

G. Preparation of Compounds of Formula (Ih) and (Ij)

Compounds of formula (Ih) and (Ij) are compounds of the invention whereR¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where R⁷ is hydrogen or alkyl, R¹⁰ ishydrogen, alkyl, aryl or aralkyl, and R¹¹ is --C(O)--R¹⁵ where R¹⁵ is--R⁸ --OR⁵, --R⁸ --N(R⁵)R⁶ or heterocyclylalkyl (optionally substitutedby alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or--C(O)N(R⁵)R⁶ (where R⁵ and R⁶ are as described above in the Summary ofthe Invention for compounds of formula (I))). These compounds areprepared as described below where A is ═CH-- or ═N--; R^(1a), R^(2a),R⁴, R⁵, R^(5a) are as described above in Reaction Scheme 1; and R⁷ andR⁸ are as described in the Summary of the Invention for compounds offormula (I); and R^(15c) is --OR⁵, --N(R⁵)R⁶ or heterocyclyl (optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶ or --C(O)N(R⁵)R⁶ (where R⁵ and R⁶ are as described above inthe Summary of the Invention for compounds of formula (I))), forexample, 4-methylpiperidine; and each X is independently bromo orchloro: ##STR39##

Compounds of formula (Q) and formula (R) are commercially available ormay be prepared by methods known to those skilled in the art.

In general, the compounds of formula (Ij) are prepared by first treatinga compound of formula (Ie) in an aprotic solvent, such as methylenechloride, in the presence of a base, such as diisopropylethylamine, attemperatures of between about -10° C. and about 10° C., preferably atabout 0° C., with a compound of formula (Q). The reaction mixture wasallowed to warm to ambient temperature and stirred for about 4 to about10 hours, preferably for about 7 hours. A compound of formula (R) isthen added to the reaction mixture and the resulting reaction mixture isstirred about 10 to about 20 hours, preferably for about 16 hours. Thecompound of formula (Ij) is isolated from the reaction mixture bystandard isolation techniques, such as concentration and purification byHPLC.

Alternatively, the compound of formula (Q) could be phosgene(Cl--C(O)--Cl). Under these circumstances, the final product would havethe R^(15c) substituent directly attached to the carbonyl in thecompound of formula (Ij). Alternatively, the compound of formula (Q)could also be X--S(O)₂ --R⁸ --X to produce compounds of the inventionwhere R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where R¹⁰ is as described above forcompounds of formula (Ij) and R¹¹ is --S(O)₂ --R¹⁵ where R¹⁵ is asdescribed above for R¹⁵.

H. Preparation of Compounds of Formula (Ik)

Compounds of formula (Ik) are compounds of the invention where R¹⁴ is--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R⁵)R⁶ where each R⁵ is as described in theSummary of the Invention for compounds of formula (I), where R⁶ and R⁷are as described in the Summary of the Invention for compounds offormula (I), R¹⁰ is hydrogen, alkyl, aryl or aralkyl, and R¹⁷ ishydrogen, alkyl, aryl or aralkyl. They are prepared as illustrated belowin Reaction Scheme 8 where A is ═CH-- or ═N--; R^(1a), R^(2a), R⁴, R⁵and R^(5a) are as described above in Reaction Scheme 1; R⁶ and R⁷ are asdescribed in the Summary of the Invention for compounds of formula (I);R¹⁰ is hydrogen, alkyl, aryl or aralkyl; R¹⁷ is hydrogen, alkyl, aryl oraralkyl; and X is bromo or chloro, or X can also be other leaving groupssuch as alkylthio (methylthio) or pyrazolyl: ##STR40##

Compounds of formula (S) are commercially available, or may be preparedaccording to methods known to those skilled in the art.

In general, compounds of formula (Ik) are prepared by treating acompound of formula (Ie) in an aprotic solvent, such as DMF, in thepresence of a base, such as triethylamine, with a compound of formula(S). The reaction mixture is stirred at ambient temperature to about 50°C., preferably at about 45° C., for about 2 to about 4 hours, preferablyfor about 3 hours. The reaction mixture is allowed to cool to ambienttemperature and acidified, preferably with trifluoroacetic acid. Thecompound of formula (Ik) is isolated from the reaction mixture bystandard isolation techniques, such as purification by HPLC.

I. Preparation of Compounds of Formula (Im)

Compounds of formula (Im) are compounds of the invention where R¹⁴ is--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰ where R⁷ is as described in the Summaryof the Invention for compounds of formula (I) and each R¹⁰ and R¹⁷ areindependently hydrogen, alkyl, aryl or aralkyl. They are prepared asillustrated below in Reaction Scheme 9 where A is ═CH-- or ═N--; R^(1a),R^(2a), R⁴, each R⁵ and R^(5a) are as described above in Reaction Scheme1; R⁷ is as described in the Summary of the Invention for compounds offormula (I); R¹⁰ and R¹⁷ are each independently hydrogen, alkyl, aryl oraralkyl; and R²⁰ is alkyl: ##STR41##

Compounds of formula (T) are commercially available or may be preparedaccording to methods known to those skilled in the art, or by methodsdescribed herein. Compounds of formula (Ie) are prepared herein.

In general, compounds of formula (Im) are prepared by treating acompound of formula (Ie) in a protic solvent, such as methanol, with acompound of formula (T). The reaction mixture is stirred at ambienttemperature for about 8 to about 20 hours, preferably for about 16hours. The compound of formula (Im) is then isolated from the reactionmixture by standard isolation techniques, such as concentration andpurification by HPLC.

J. Preparation of Compounds of Formula (In) and (Io)

Compounds of formula (In) are compounds of the invention where R¹⁴ is--C(R⁷)H--N(R¹⁰)R¹¹ where R⁷ is hydrogen or alkyl, R¹⁰ is hydrogen,alkyl, aryl or aralkyl and R¹¹ is --C(O)--N(R⁵)R¹⁵ or --C(S)--N(R⁵)R¹⁵ ;and compounds of formula (Io) are compounds of the invention where R¹⁴is --C(R⁷)H--N(R¹⁰)R¹¹ where R⁷ is hydrogen or alkyl and R¹⁰ ishydrogen, alkyl, aryl or aralkyl, and R¹¹ is heterocyclyl (optionallysubstituted by alkyl or oxo). They are prepared as illustrated belowwhere A is ═CH-- or ═N--; R^(1a), R^(2a), R⁴, each R⁵ and R^(5a) are asdescribed above in Reaction Scheme 1; R⁷ is as described in the Summaryof the Invention for compounds of formula (I); R¹⁰ is hydrogen, alkyl,aryl or aralkyl; Z is oxygen or sulfur; n is 2 or 3; and X is bromo orchloro: ##STR42##

Compounds of formula (U) are commercially available or may be preparedaccording to methods known to those skilled in the art. Compounds offormula (Ie) are prepared herein.

In general, compounds of formula (Io) are prepared by first treating acompound of formula (Ie) in an aprotic solvent, such as tetrahydrofuran,at temperatures of about -10° C. to about 10° C., preferably at about 0°C., with an excess molar amount of a compound of formula (U). Thereaction mixture is stirred at ambient temperature for about 4 to 10hours, preferably for about 7 hours to form a compound of formula (In).The reaction mixture is cooled to a temperature of about -10° C. toabout 10° C., preferably to about 0° C., and a mild base, preferablytriethylamine, is added to the reaction mixture. The resulting reactionmixture is then warmed to ambient temperature and stirred for about 20to 30 hours, preferably for about 24 hours. The compound of formula (Io)is then isolated from the reaction mixture by standard isolationtechniques, such as concentration of volatiles and purification by flashchromatography.

Other compounds of formula (U) may be used to produce compounds offormula (Io) wherein the heterocyclyl ring so formed is substituted byalkyl or by oxo. For example, if the nitrogen of the isocyanate issubstituted by a branched alkyl with the terminal halo atom being 2 to 3carbons away from the nitrogen, the compound so formed would have analkyl substituent off the heterocyclic ring in the compound of formula(Io). Also, if the nitrogen is substituted by --C(O)--R¹⁷ where R¹⁷ is ahaloalkyl (where the halo is on the terminal carbon of the haloalkylgroup), one would end up with a heterocyclic ring with an oxosubstituent next to the nitrogen atom of the heterocyclic.

K. Preparation of Compounds of Formula (Z)

Compounds of formula (Z) are intermediates in the preparation of thecompounds of the invention and are prepared as illustrated below whereR^(5a) is alkyl, R⁷ is hydrogen or alkyl, R^(13a) hydrogen, halo, --OR⁵(where R⁵ is alkyl, aryl or aralkyl); and R^(14a) is as described abovein Reaction Scheme 1; and each X is bromo or chloro: ##STR43##

Compounds of formula (V) and formula (H) are commercially available ormay be prepared according to methods known to those skilled in the artor methods disclosed herein.

In general, compounds of formula (Z) are prepared by first reacting acompound of formula (V) in an aprotic solvent, such as carbontetrachloride, with a halogenating agent, such as sulfuryl chloride, inthe presence of a catalytic agent, such as benzoyl peroxide. Thereaction mixture is heated at reflux for about 12 to about 20 hours,preferably for about 17 hours, then cooled to ambient temperature. Thecompound of formula (W) is then isolated from the reaction mixture bystandard isolation techniques, such as concentration of volatiles andpurification by flash chromatography.

The compound of formula (W) in an aprotic solvent, such as methylenechloride, is then treated with a compound of formula (H). The resultingreaction mixture is then stirred at ambient temperature for about 10 toabout 20 hours, preferably for about 16 hours. The compound of formula(X) is then isolated from the reaction mixture by standard isolationtechniques, such as concentration of the product and purification byflash chromatography.

The compound of formula (X) in a protic solvent, such as ethanol, isthen hydrolyzed under basic hydrolysis conditions (for example, by theaddition of a strong base, such as sodium hydroxide) at ambienttemperature. The compound of formula (Y) is then isolated from thereaction mixture by standard isolation techniques, such as concentrationof volatiles, dissolution of product in water, acidification of theaqueous solution with a strong acid and filtration.

The compound of formula (Y) is then converted to a compound of formula(Z) by standard techniques.

Alternatively, the compound of formula (Y) can be isolated as the metalsalt and then converted as is to a compound of formula (Z) by standardtechniques.

Compounds of formula (Z) may be then be reacted with compounds offormula (E) to prepare compounds of the invention as described above inReaction Scheme 1.

L. Preparation of Compounds of Formula (Iq)

Compounds of formula (Iq) are compounds of the invention wherein R² is--O--R⁸ --N(R¹⁰)R¹¹ where R⁸ is as defined in the Summary of theInvention for compounds of formula (I) and R¹⁰ and R¹¹ are as defined inthe Summary of the Invention for compounds of formula (I) except thatneither can be --OR⁵, --S(O)₂ --R¹⁵, --C(O)--R¹⁵, --C(O)--N(R⁵)R¹⁵ or--C(S)--N(R⁵)R¹⁵. They are prepared as illustrated below in ReactionScheme 12 where A is ═CH-- or ═N--; R^(1a), R⁴ and R¹⁴ are as describedin the Summary of the Invention for compounds of formula (I) except thatnone can be hydroxy, amino, carboxy or contain a nucleophilic amine; andR⁵ and R⁸ are as described in the Summary of the Invention for compoundsof formula (I); and R^(2b) is --N(R¹⁰)R¹¹ where R¹⁰ and R¹¹ are asdefined above; and R¹³ is as described in the Summary of the Inventionfor compounds of formula (I) except that R¹³ can not be haloalkyl wherethe alkyl is substituted by only one halogen atom or R¹³ can not containa nucleophilic nitrogen, and each X is bromo or chloro: ##STR44##

Compounds of formula (AA) and (CC) are commercially available. Compoundsof formula (Ip) are prepared by methods disclosed herein.

In general, compounds of formula (Iq) are prepared by treating acompound of formula (Ip) in an aprotic solvent, such as DMF, in thepresence of a base, such as cesium carbonate, with a compound of formula(AA). The reaction mixture is stirred at ambient temperature for about16 to about 20 hours to make the compound of formula (BB). A compound offormula (CC) is added to the reaction mixture and the resulting reactionmixture is heated to temperatures of between about 60° C. and 70° C.,preferably to about 65° C. The reaction mixture is maintained at thattemperature for about 10 to about 14 hours, preferably for about 12hours. The reaction mixture is then cooled to ambient temperature andthe compound of formula (Iq) is isolated from the reaction mixture bystandard isolation techniques, such as filtration and purification byHPLC.

When the compound of formula (CC) is a non-reactive amine, the anion ofthe amine may be prepared prior to reacting with the compound of formula(BB) to form the compound of formula (Iq). Such non-reactive aminesinclude, but are not limited to, imidazole, tetrazole, and pyrazole.

M. Preparation of Compounds of Formula (Ir)

Compounds of formula (Ir) are compounds of the invention wherein R² is--O--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --OR⁹, --O--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), --O--R⁸ --C(O)OR⁵, --O--R⁸ --N(R¹⁰)R¹¹,--O--C(O)--R⁵ where each R⁵, R⁹ and R⁸ are as defined above in theSummary of the Invention for compounds of formula (I); and R¹⁰ and R¹¹are as defined above in the Summary of the Invention for compounds offormula (I). They are prepared as illustrated below in Reaction Scheme13 where A is ═CH-- or ═N--; R^(1a), R⁴ and R¹⁴ are as described in theSummary of the Invention for compounds of formula (I) except that nonecan be hydroxy, amino, carboxy or contain a nucleophilic amine; and R⁵and R⁸ are as defined in the Summary of the Invention for compounds offormula (I), and R¹³ is as described in the Summary of the Invention forcompounds of formula (I) except that R¹³ can not be haloalkyl where thealkyl is substituted by only one halogen atom or R¹³ can not contain anucleophilic nitrogen, and R^(2c) is --R⁸ --S(O)_(p) --R⁹ (where p is 0to 2), --R⁵, --(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --R⁸ --C(O)OR⁵,--R⁸ --N(R¹⁰)R¹¹, --C(O)--R⁹ where each R⁵, R⁸, R⁹, R¹⁰ and R¹¹ are asdefined above; and X is chloro or bromo: ##STR45##

Compounds of formula (DD) are commercially available or may be preparedaccording to methods known to those of ordinary skill in the art.Compounds of formula (Ip) are prepared herein.

In general, compounds of formula (Ir) are prepared by treating acompound of formula (Ip) in an aprotic solvent, such as DMF, in thepresence of a strong base, such as sodium hydride, at ambienttemperature with a compound of formula (DD). The reaction mixture isstirred for about 1 hour to about 4 hours, preferably for about 3 hours,and then cooled to temperatures of between about -10° C. and 10° C.,preferably to 0° C. The reaction mixture is then acidified with a mildacid, such as trifluoroacetic acid. The compound of formula (Ir) is thenisolated from the reaction mixture by standard isolation techniques,such as purification by HPLC.

Alternatively, compounds of formula (Ir) may be prepared by treating acompound of formula (Ip) in an aprotic solvent, such as DMF, in thepresence of a strong base, such as cesium carbonate, at ambienttemperature with a compound of formula (DD). The reaction mixture isthen heated to between about 50° C. and about 65° C., preferably toabout 60° C. and stirred at that temperature for about 10 to about 20hours, preferably for about 16 hours. The reaction mixture is thenallowed to cool to ambient temperature and filtered. The resultingfiltrate is then acidified by a mild acid, such as trifluoroacetic acid,and the compound of formula (Ir) is isolated from the reaction mixtureby standard isolation techniques, such as purification by HPLC.

N. Preparation of Compounds of Formula (Is)

Compounds of formula (Is) are compounds of the invention wherein R² is--O--R⁸ --CH(OH)--CH₂ --N(R¹⁰)R¹¹ where R¹⁰ and R¹¹ are as defined abovein the Summary of the Invention for compounds of formula (I) except thatneither can be --OR⁵, --S(O)₂ --R¹⁵, --C(O)--R¹⁵, --C(O)--N(R⁵)R¹⁵ or--C(S)--N(R⁵)R¹⁵. They are prepared as illustrated below in ReactionScheme 14 where A is ═CH-- or ═N--; R^(1a), R⁴ and R¹⁴ are as describedin the Summary of the Invention for compounds of formula (I) except thatnone can be hydroxy, amino, carboxy or contain a nucleophilic amine; andR⁵ and R⁸ are as described in the Summary of the Invention for compoundsof formula (I); and R^(2b) is --N(R¹⁰)R¹¹ where R¹⁰ and R¹¹ are asdefined above; and R¹³ is as described in the Summary of the Inventionfor compounds of formula (I) except that R¹³ can not be haloalkyl wherethe alkyl is substituted by only one halogen atom or R¹³ can not containa nucleophilic nitrogen; and each X is bromo or chloro: ##STR46##

Compounds of formula (EE) and (CC) are commercially available or may beprepared according to methods known to those skilled in the art.Compounds of formula (Ip) are prepared herein.

In general, compounds of formula (Is) are prepared by first treating acompound of formula (Ip) in an aprotic solvent, such as DMF, with acompound of formula (EE) in the presence of strong base, such as cesiumcarbonate. The reaction mixture is stirred at ambient temperature forabout 3 days. The compound of formula (FF) is then isolated from thereaction mixture by standard isolation techniques such as filtration andconcentration.

The compound of formula (FF) in an aprotic solvent, preferably DMF, isthen treated with salt of a compound of formula (CC). The reactionmixture is stirred at ambient temperature for about 16 to about 20hours, preferably for about 18 hours. The compound of formula (Is) isthen isolated from the reaction mixture by standard isolationtechniques, such as concentration of volatiles and purification by HPLC.

O. Preparation of Compounds of Formula (It)

Compounds of formula (It) are compounds of the invention wherein R² is--O--R⁸ --CH(OH)--CH₂ --OR⁵ where R⁵ and R⁸ are as defined in theSummary of the Invention for compounds of formula (I). They are preparedas illustrated in the following Reaction Scheme 15 where A is ═CH-- or═N--; R^(1a), R⁴ and R¹⁴ are as described in the Summary of theInvention for compounds of formula (I) except that none can be hydroxy,amino, carboxy or contain a nucleophilic amine; and R⁵, and R⁸ are asdescribed in the Summary of the Invention for compounds of formula (I);and R¹³ is as described in the Summary of the Invention for compounds offormula (I) except that R¹³ can not be haloalkyl where the alkyl issubstituted by only one halogen atom or R¹³ can not contain anucleophilic nitrogen; and each X is bromo or chloro: ##STR47##

Compounds of formula (FF) are prepared herein. Compounds of formula (HH)are commercially available or may be prepared according to methods knownto those skilled in the art.

In general, compounds of formula (It) are prepared by treating acompound of formula (FF) in an aprotic solvent, such as methylenechloride, with an excess amount of a compound of formula (HH) in thepresence of an oxidant, such as dichlorodicyanobenzoquinone. Thereaction mixture is stirred at ambient temperature for about 24 to about48 hours, preferably for about 48 hours. The reaction is then quenchedwith the addition of a mild base, such as aqueous sodium bicarbonate.The compound of formula (It) is isolated from the reaction mixture bystandard isolation techniques, such as extraction, concentration ofvolatiles and purification by flash chromatography.

P. Preparation of Compounds of Formula (Iv)

Compounds of formula (Iv) are compounds of the invention wherein the R²substituent is in the 4-position and is --S--R⁹, --N(R¹⁰)R¹¹,--N(R⁵)--R⁸ --N(R¹⁰)R¹¹, --S--R⁸ --N(R⁵)R⁶, --S--R⁸ --C(O)OR⁵, or--N(R⁵)--CH(R¹²)--C(O)OR⁵ (where R⁵, R⁶, R⁸, R⁹ and R¹² are as definedin the Summary of the Invention for compounds of formula (I) and R¹⁰ andR¹¹ are as defined in the Summary of the Invention for compounds offormula (I) except that neither can be --OR⁵, --S(O)₂ --R¹⁵,--C(O)--R¹⁵, --C(O)N(R⁵)R¹⁵ or --C(S)--N(R⁵)R¹⁵ when R² is --N(R¹⁰)R¹¹).They are prepared as illustrated below in Reaction Scheme 16 whereinR^(1a) is halo; and R⁴ and R¹⁴ are as described in the Summary of theInvention for compounds of formula (I) except that neither can contain anucleophilic amine; and R⁵ is as described in the Summary of theInvention for compounds of formula (I); and R¹³ is as described in theSummary of the Invention for compounds of formula (I) except that R¹³can not be haloalkyl where the alkyl is substituted by only one halogenatom or R¹³ can not contain a nucleophilic nitrogen; and R^(2d) is--S--R⁹, --N(R¹⁰)R¹¹, --N(R⁵)--R⁸ --N(R¹⁰)R¹¹, --S--R⁸ --N(R⁵)R⁶,--S--R⁸ --C(O)OR⁵, or --N(R⁵)--CH(R¹²)--C(O)OR⁵ (where R⁵, R⁶, R⁸, R⁹,R¹⁰, R¹¹ and R¹² are as defined above for R²): ##STR48##

Compounds of formula (II) are commercially available, or may be preparedaccording to methods known to those skilled in the art. Compounds offormula (Iu) may be prepared according to methods disclosed herein.

In general, compounds of formula (Iv) are prepared by treating acompound of formula (Iu) with a compound of formula (II) in the presenceof a base. The reaction mixture is heated to temperatures of betweenabout 80° C. and about 105° C., preferably at about 85° C., for about 10to about 20 hours, preferably for about 15 hours. The compound offormula (Iv) is then isolated from the reaction mixture by standardisolation techniques, such as concentration and purification by HPLC.

Q. Preparation of Compounds of Formula (Ip)

Compounds of formula (Ip) are compounds of the invention wherein R² ishydroxy. These compounds are prepared as illustrated below where A is═CH-- or ═N--; and R¹, R⁴, R⁵, R¹³, R¹⁴, m and n are as defined above inthe Summary of the Invention for compounds of formula (I): ##STR49##

Compounds of formula (Iw) are compounds of the invention which areprepared by the methods disclosed herein.

In general, compounds of formula (Ip) are prepared by treating acompound of formula (Iw) in an aprotic solvent, such as methylenechloride, with boron tribromide at ambient temperature. The reactionmixture is stirred for about 10 to about 20 hours, preferably for about18 hours. The compound of formula (Ip) is then isolated from thereaction mixture by standard isolation techniques, such as extractionand concentration.

During this reaction, if any of the other substituents, such as R¹, R⁴,etc., contain an ester group or a lower alkyl ether group, the estergroup will also be hydrolyzed to the corresponding acid and the ethergroup will be hydrolyzed to the corresponding alcohol.

R. Preparation of Compounds of Formula (Eb)

Compounds of formula (Eb) are compounds of formula (E) wherein R^(1a) isin the 5-position and is halo. These compounds, which are intermediatesin the preparation of the compounds of the invention, may be prepared asillustrated below in Reaction Scheme 18 where A is ═CH-- or ═N--; R²,R⁴, and R⁵ are as described above in the Summary of the Invention forcompounds of formula (I); and R^(5a) is hydrogen, and X is chloro orbromo: ##STR50##

Compounds of formula (Ea) are prepared by methods disclosed herein.

In general; compounds of formula (Eb) are prepared by treating acompound of Ea in an organic solvent, such as benzene, with ahalogenating agent. The reaction mixture is heated to temperatures ofabout 45° C. to about 55° C., preferably to about 50° C. to about 55° C.The reaction mixture is allowed to cool to ambient temperature and thecompound of formula (Eb) is then isolated from the reaction mixture bystandard isolation techniques, such as concentration, extraction andrecrystallization.

S. Preparation of Compounds of Formula (Db)

Compounds of formula (Db) are compounds of formula (D) where the R^(1a)substituent is in the 5-position and is chloro and R² is in the3-position and is --N(R¹⁰)R¹¹, --N(R⁵)--R⁸ --N(R¹⁰)R¹¹,--N(R⁵)--CH(R¹²)--C(O)OR⁵ (where R⁵, R⁸, R¹⁰, R¹¹ and R¹² are as definedin the Summary of the Invention for compounds of formula (I) except thatR¹⁰ and R¹¹ can not be --S(O)₂ --R¹⁵, --C(O)--R¹⁵, --C(O)N(R⁵)R¹⁵ or--C(S)N(R⁵)R¹⁵ when R² is --N(R¹⁰)R¹¹). These compounds, which areintermediates in the preparation of the compounds of the invention, areprepared as illustrated below in Reaction Scheme 19 where A is ═CH-- or═N--; R⁴ and R⁵ are as described in the Summary of the Invention forcompounds of formula (I); and R^(2e) is --N(R¹⁰)R¹¹, --N(R⁵)--R⁸--N(R¹⁰)R¹¹, or --N(R⁵)--CH(R¹²)--C(O)OR⁵ (where R⁵, R⁸, R¹⁰, R¹¹, andR¹² are as defined above for R²): ##STR51##

Compounds of formula (Da) are prepared by methods described herein.Compound of formula (JJ) are commercially available or may be preparedaccording to methods known to those skilled in the art.

In general, compounds of formula (Db) are prepared by treating acompound of formula (Da) in a polar aprotic solvent, such as DMSO, witha compound of formula (JJ) in the presence of a base, such asdiisopropylethylamine. The reaction mixture is heated to temperatures ofbetween about 100° C. to about 120° C., preferably to about 110° C. toabout 120° C. and maintained at that temperature for about 3 to about 5hours, preferably for about 4 hours. The reaction mixture is then cooledto ambient temperature and the compound of formula (Db) is isolated fromthe reaction mixture by standard isolation techniques such asextraction, concentration and purification by flash chromatography.

T. Preparation of Compounds of Formula (Ec)

Compounds of formula (Ec) are compounds of formula (E) where R^(1a) ishydrogen. These compounds, which are intermediates in the preparation ofthe compounds of the invention, may be prepared as illustrated below inReaction Scheme 20 where A is ═CH-- or ═N--; R^(1a) is hydrogen, alkyl,aryl, aralkyl, halo, cyano, --OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2),--C(O)OR⁵, --C(O)--N(R⁵)R⁶ and --N(R⁵)R⁶ (where each R⁵ and R⁶ can notbe hydrogen and R⁹ is alkyl, aryl, or aralkyl); and R^(2a) is as definedabove in Reaction Scheme 1, and R⁴ and R⁵ are as defined above in theSummary of the Invention for compounds of formula (I): ##STR52##

Compounds of formula (KK) and formula (C) and phosgene are commerciallyavailable or may be prepared according to methods known to those skilledin the art.

In general, compounds of formula (Ec) are prepared by first treating acompound of formual (KK) with phosgene in an aprotic solvent, such asdioxane. The reaction mixture is stirred at ambient temperature to about70° C., preferably at about 65° C., for about 8 to about 12 hours,preferably for about 10 hours. The reaction mixture is cooled to ambienttemperature and the compound of formula (LL) is then isolated from thereaction mixture by standard isolation techniques, such as filtrationand evaporation of solvents.

The compound of formula (LL) in a polar aprotic solvent, such asdioxane, is treated with a compound of formula (C). The reaction mixtureis heated at reflux for about 10 to about 20 hours, preferably for about15 hours. The reaction mixture is allowed to cool to ambient temperatureand the compound of formula (Ec) is then isolated from the reactionmixture by standard isolation techniques, such as filtration andconcentration.

U. Preparation of Compounds of Formula (F)

Compounds of formula (F) are intermediates used to prepare compounds ofthe invention and may be prepared as illustrated below in ReactionScheme 21 wherein each R⁵ is alkyl, R⁷ is hydrogen or alkyl; and M is ametal cation and X is bromo or chloro: ##STR53##

Compounds of formula (MM) are commercially available or may be preparedaccording to methods disclosed herein or by standard methods known tothose of ordinary skill in the art.

In general, compounds of formula (F) are prepared by first treating acompound of formula (MM) in a similar manner as that described hereinfor the preparation of compounds of formula (W) to prepare a compound offormula (NN).

The compound of formula (NN) in a mild acidic aqueous solution is thentreated with a compound of formula (SS). The reaction mixture is heatedto reflux for about 20 hours to about 30 hours, preferably for about 24hours. The reaction mixture is then cooled to ambient temperature andthe compound of formula (OO) is then isolated from the reaction mixtureby standard isolation techniques, such as concentration and extraction.

The compound of formula (OO) is then hydrolyzed under standard basicconditions to produce the compound of formula (PP). The compound offormula (PP) may be isolated as the metal salt and may be used as suchin the next step.

The compound of formula (PP) is then converted to the acid halide bytreatment with the appropriate agent, such as thionyl chloride orthionyl bromide. The resulting compound of formula (F) is isolated fromthe reaction mixture by standard isolation techniques.

V. Preparation of the Compound of Formula (RR)

The compound of formula (RR) is an intermediate in the preparation ofcompounds of the invention and is prepared as illustrated below inReaction Scheme 22: ##STR54##

The compound of formula (QQ) is commercially available.

In general, the compound of formula (RR) is prepared by treating thecompound of formula (QQ) in the presence of a mild acid, such astrifluoroacetic acid, with nitric acid. The reaction mixture is stirredat temperatures of between about -10° C. and 10° C., preferably at about0° C., for about 30 minutes to an hour, preferably for about 1 hour. Thereaction mixture is warmed to ambient temperature and stirred for about2 to about 4 hours, preferably for about 3 hours. The compound offormula (RR) is then isolated from the reaction mixture by standardisolation techniques, such as precipitation and filtration.

All compounds of the invention as prepared above which exist in freebase or acid form may be converted to their pharmaceutically acceptablesalts by treatment with the appropriate inorganic or organic base oracid. Salts of the compounds prepared above may be converted to theirfree base or acid form by standard techniques.

The following specific preparations and examples are provided as a guideto assist in the practice of the invention, and are not intended as alimitation on the scope of the invention.

PREPARATION 1 Compounds of Formula (B)

A. To a suspension of 5-chloro-2-nitrobenzoic acid (21 g, 100 mmol) indry methylene chloride (200 mL) at 0° C. were added several drops ofDMF, followed by oxalyl chloride (13 mL, 150 mmol). The reaction waswarmed to ambient temperature. After 16 hours the solvents were removedand the viscous oil dried in vacuo to afford 23 g (quantitative yield)of 5-chloro-2-nitrobenzoyl chloride; NMR (CDCl₃) 8.1 (d, 1), 7.7 (m, 2)ppm.

B. In a similar manner, the following compounds were made:

3,5-dichloro-2-nitrobenzoyl chloride;

5-methyl-2-nitrobenzoyl chloride;

5-(chloro)carbonyl-6-nitro-1,3-benzodioxole;

3-methoxy-2-nitrobenzoyl chloride; and

4,5-dimethoxy-2-nitrobenzoyl chloride.

C. In a similar manner, other compounds of formula (B) and correspondingintermediates of the compounds of the invention may be prepared.

PREPARATION 2 Compounds of Formula (D)

A. To a solution of 5-chloro-2-nitrobenzoyl chloride (23 g, 100 mmol) inmethylene chloride (200 mL) at 0° C. was added triethylamine (16 mL, 115mmol), followed by 4-chloroaniline (14 g, 110 mmol). The mixture wasstirred for 20 minutes at 0° C., then warmed to ambient temperature.After 5 hours, the mixture was concentrated of all volatiles in vacuo.The residual solid was dissolved in ethyl acetate (400 mL) and washedwith water (200 mL), 1M hydrochloric acid (2×200 mL), 1M sodiumbicarbonate (200 mL) and brine (200 mL) and dried over MgSO₄.Concentration and drying in vacuo afforded 30 g (93% yield) ofN-(4-chlorophenyl)-5-chloro-2-nitrobenzamide; NMR (CDCl₃) 8.1 (d, 1),7.7 (br, 1), 7.6 (m, 2), 7.5 (d, 2), 7.3 (d, 2) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-3,5-dichloro-2-nitrobenzamide; NMR (CDCl₃) 8.4(s, 1), 8.0-8.2 (m, 3), 7.9 (m, 1) ppm;

N-(4-chlorophenyl)-4,5-dimethoxy-2-nitrobenzamide; NMR (DMSO-d₆ /TFA)10.6 (s, 1), 7.7 (d, 2), 7.6 (s, 1), 7.4 (d, 2), 7.2 (s, 1), 4.0 (s, 3),3.9 (s, 3) ppm;

N-(4-chlorophenyl)-3-methoxy-2-nitrobenzamide; NMR (DMSO-d₆ /TFA) 10.8(s, 1), 7.7 (m, 3), 7.5 (d, 1), 7.4 (t, 2), 3.9 (s, 3), 3.4 (br s, 1)ppm;

N-(5-chloropyridin-2-yl)-3-methoxy-2-nitrobenzamide; NMR (CDCl₃) 8.8(br, 1), 8.3 (d, 1), 8.1 (s, 1), 7.7 (d, 1), 7.5 (t, 1), 7.3 (m, 2), 3.9(s, 3) ppm;

N-(5-chloropyridin-2-yl)-5-chloro-2-nitrobenzamide;

N-(5-bromopyridin-2-yl)-5-chloro-2-nitrobenzamide;

N-(4-chlorophenyl)-5-methyl-2-nitrobenzamide;

N-(4-bromophenyl)-5-methyl-2-nitrobenzamide;

N-(pyridin-2-yl)-5-chloro-2-nitrobenzamide;

5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-nitro-1,3-benzodioxole; and

N-(4-chlorophenyl)-3-nitro-pyridin-2-amide.

C. In a similar manner, other compounds of formula (D) and correspondingintermediates of the compounds of the invention may be prepared.

PREPARATION 3 Compounds of Formula (E)

A. N-(4-Chlorophenyl)-5-chloro-2-nitrobenzamide (13.2 g, 42.4 mmol) andtin(II) chloride dihydrate (48 g, 213 mmol) were combined in ethylacetate (90 mL) and the mixture was heated at 70° C. under a nitrogenatmosphere. After 15 minutes, the mixture was cooled to ambienttemperature, then poured onto water (750 mL) and ethyl acetate (750 mL).The aqueous layer was adjusted to pH 8 with by addition of 1 N NaOH anda saturated NaHCO₃ solution, and the layers were separated. The aqueouslayer was further extracted with 500 mL of ethyl acetate. The combinedorganic extracts were washed with water (1 L), then brine (500 mL),dried over MgSO₄, filtered, and concentrated in vacuo to afford 11.6 g(97% yield) of N-(4-chlorophenyl)-2-amino-5-chlorobenzamide as anoff-white solid; NMR (CDCl₃) 7.7 (br s, 1), 7.2-7.5 (m, 6), 6.7 (d, 1),5.5 (br s, 2) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2,3-diamino-5-chlorobenzamide; NMR (DMSO-d₆/TFA) 10.6 (s, 1), 8.4 (dd, 1), 8.0 (dd, 1), 7.8 (m, 1), 7.8 (d, 1), 7.2(dd, 1), 7.1 (m, 1), 6.8 (d, 1), 6.5 (s, 2) ppm;

N-(5-chloropyridin-2-yl)-2-amino-3-dimethylamino-5-chlorobenzamide; NMR(CDCl₃) 8.5 (s, 1), 8.3 (d, 1), 8.2 (d, 1), 7.7 (dd, 1), 7.3 (d, 1), 7.1(d, 1), 6.0 (br s, 2), 2.7 (s, 6) ppm;

N-(5-chloropyridin-2-yl)-2-amino-3-(morpholin-4-yl)-5-chlorobenzamide;NMR (CDCl₃) 8.3 (m, 1), 7.5 (m, 1), 7.1-7.4 (m, 3), 3.9 (m, 4), 3.2 (m,4) ppm;

N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide;

N-(5-bromopyridin-2-yl)-2-amino-5-chlorobenzamide;

N-(4-chlorophenyl)-2-amino-5-methylbenzamide;

N-(4-bromophenyl)-2-amino-5-methylbenzamide;

N-(5-chloropyridin-2-yl)-2-amino-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;

N-(4-chlorophenyl)-2-amino-5-chloro-3-(morpholin-4-yl)benzamide;

N-(5-chloropyridin-2-yl)-2-amino-3-(4-ethylpiperazin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-amino-3-(4-(ethoxycarbonylpiperidin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-amino-5-(N'-methyl-N'-(ethoxycarbonylmethyl)amino)-3-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-amino-3-(N',N'-di(2-methoxyethyl)amino)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-amino-3-(pyrrolidin-1-yl)-5-chlorobenzamide;

5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-amino-1,3-benzodioxole.

C. In a manner similar to that described in Paragraph A above,N-(5-chloropyridin-2-yl)-2-nitro-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide(13 g, 26 mmol) was reacted with tin(II) chloride dihydrate (29 g, 130mmol) in pyridine (100 mL) to afford 7.1 g (60% yield) ofN-(5-chloropyridin-2-yl)-2-amino-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide,as a yellow solid; NMR (DMSO-d₆) 10.8 (s, 1), 8.4 (d, 1), 8.1 (d, 1),7.9 (dd, 1), 7.6 (d, 1), 7.1 (d, 1), 6.2 (d, 2), 3.3 (m, 4), 2.7 (br,4), 1.4 (s, 9) ppm.

D. To a solution of sodium hydrosulfite (300 g, 1.7 mol) in water (4 L)was added N-(5-chloropyridin-2-yl)-2-nitro-3-methoxybenzamide (140 g,0.45 mol). Tetrahydrofuran (2 L) and 1,4-dioxane (2 L) were added andthe resulting mixture stirred at ambient temperature. After 16 hours,the solution was made basic by addition of potassium carbonate and thephases separated. The organic phase was concentrated of all volatiles invacuo to give an off-white solid. The solid was washed with water,filtered, and dried under vacuum to afford 111 g (88% yield) ofN-(5-chloropyridin-2-yl)-2-amino-3-methoxybenzamide; NMR (CDCl₃) 8.8(br, 1), 8.3 (d, 1), 8.1 (s, 1), 7.7 (dd, 1), 7.1 (dd, 1), 6.8 (d, 1),6.6 (t, 1), 5.9 (br, 1), 3.9 (s, 3) ppm.

E. In a similar manner, the following compound was made:

N-(4-chlorophenyl)-2-amino-3-methoxybenzamide.

F. To a suspension of N-(4-bromophenyl)-2-nitro-5-chlorobenzamide (0.50g, 1.4 mmol) in methanol (20 mL) was added 5% platinum on carbon(Degussa type, 50% water, 0.20 g), and the mixture stirred underhydrogen (balloon). After 0.5 hours, the mixture was filtered andconcentrated of all volatiles in vacuo to afford 0.45 g (99% yield) ofN-(4-bromophenyl)-2-amino-5-chlorobenzamide as a white solid; NMR(DMSO-d₆) 10.2 (s, 1), 7.5-7.7 (m, 5), 7.2 (dd, 1), 6.8 (d, 1) ppm.

G. In a similar manner, the following compounds were made:

N-phenyl-2-amino-4,5-dimethoxybenzamide;

N-(5-chloropyridin-2-yl)-2-amino-5-methylbenzamide;

N-phenyl-2-amino-5-methylbenzamide;

N-(4-chlorophenyl)-3-aminopyridin-2-amide.

H. In a manner similar to those methods described above, other compoundsof formula (E) and corresponding intermediates of the compounds of theinvention may be prepared.

PREPARATION 4 Compounds of Formula (G)

A. To a solution of 3-chloro-4-chloromethyl-2-(chlorocarbonyl)thiophene(3.1 g, 13.5 mmol) in methylene chloride (40 mL) at 0° C. was addedN-(4-chlorophenyl)-2-amino-5-chlorobenzamide (3.8 g, 13.5 mmol),followed after 5 minutes by pyridine (1.6 mL, 16 mmol). The mixture waswarmed to ambient temperature. After 17 hours, the mixture wasconcentrated of all volatiles in vacuo. The resulting solid wastriturated with water and a small amount of acetonitrile and dried invacuo to afford 5.1 g (80% yield) ofN-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamideas a tan powder: NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 8.2(s, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 4.8 (s, 2) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (CDCl₃) 9.3 (br, 1), 9.1 (br, 1), 8.3 (d, 1), 8.0 (d, 1), 7.7 (d,1), 7.6 (s, 1), 7.2 (d, 1), 7.0 (d, 1), 4.6 (s, 2), 3.9 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;NMR (CDCl₃) 10.9 (s, 1), 9.5 (s, 1), 8.4 (s, 1), 7.8-8.2 (m, 3), 7.4 (m,2), 4.7 (s, 2), 3.7 (m, 4), 2.9 (m, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;NMR (CDCl₃) 10.8 (s, 1), 9.5 (s, 1), 8.4 (s, 1), 7.8-8.2 (m, 3), 7.4 (m,2), 4.7 (s, 2), 3.4 (m, 8), 2.9 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-ethylpiperazin-1-yl)-5-chlorobenzamide;NMR (CDCl₃) 10.7 (s, 1), 9.6 (s, 1), 8.3 (s, 1), 7.8-8.2 (m, 3), 7.5 (m,2); 4.6 (s, 2), 3.2-3.5 (m, 10), 1.4 (m, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(ethoxycarbonyl)piperidin-1-yl)-5-chlorobenzamide;NMR (CDCl₃) 10.8 (s, 1), 9.5 (s, 1), 7.1-8.4 (m, 6), 4.5 (s, 2), 3.0-3.5(m, 7), 1.8-2.2 (m, 4), 1.2 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-chloro-5-(N'-methyl-N'-(ethoxycarbonyl)methylamino)benzamide;NMR (CDCl₃) 10.9 (s, 1), 9.5 (s, 1), 8.5 (s, 1), 7.8-8.2 (m, 3), 7.5 (m,2), 4.6 (s, 2), 3.0-3.6 (m, 4), 2.9 (s, 3), 1.1 (t, 3);

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(N',N'-di(2-methoxyethyl)amino)-5-chlorobenzamide;NMR (CDCl₃) 10.8 (s, 1), 9.5 (s, 1), 7.3-8.6 (m, 6), 4.4 (s, 2), 2.8-3.5(m, 11) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-amino-5-chlorobenzamide;NMR (CDCl₃) 10.9 (s, 1), 9.7 (s, 1), 7.4-8.6 (m, 6), 4.2 (s, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.4 (s, 1), 11.0 (s, 1), 7.6-8.4 (m, 7), 4.8 (s, 2) ppm;

N-(4-chlorophenyl)-2-[((4,5-di(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.2 (s, 1), 10.7 (s, 1), 8.3 (d, 1), 7.4-7.9 (m, 6), 5.1(s, 2), 4.8 (s, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-dimethylamino-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.5 (s, 1), 9.6 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 8.0(s, 2), 7.8 (dd, 1), 7.7 (d, 1), 4.6 (s, 2), 3.0 (s, 6) ppm;

N-(pyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.6 (s, 1), 8.4 (d, 1), 8.3 (t, 1), 8.0 (d, 1), 7.9(s, 1), 7.8 (s, 1), 7.7 (d, 1), 7.6 (dd, 1), 7.5 (t, 1), 4.6 (s, 2) ppm;

N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolidin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide;

5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole;

N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-fluorobenzamide;

N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.4 (s, 1), 9.5 (s, 1), 8.1 (s, 1), 7.7 (d, 2),7.3-7.4 (m, 4), 4.8 (s, 2), 3.9 (s, 3) ppm.

C. In a manner similar to those methods described above, other compoundsof formula (G) and corresponding intermediates of the compounds of theinvention may be prepared.

PREPARATION 5 Compounds of Formula (K)

A. To a suspension ofN-(4-chlorophenyl)-2-[((5-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(2.6 g, 6.0 mmol) in dry benzene (250 mL) were added N-bromosuccinimide(1.2 g, 6.6 mmol) and benzoyl peroxide (0.15 g, 0.6 mmol). The mixturewas refluxed while irradiating with a 250 Watt lamp. After 28 hours thereaction was concentrated of all volatiles in vacuo and the resultingsolid triturated with benzene. Purification by flash chromatography onsilica gel afforded 2.3 g (75% yield) ofN-(4-chlorophenyl)-2-[((5-bromomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamideas a white solid; NMR (DMSO-d₆) 11.1 (s, 1), 10.7 (s, 1), 8.3 (d, 1),7.9 (s, 1), 7.7 (d, 2), 7.6 (d, 1), 7.4 (d, 2), 7.3 (s, 1), 4.9 (s, 2)ppm.

B. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-[((3-(bromomethyl)benzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.4 (s, 1), 10.8 (s, 1), 8.4 (d, 1), 7.4-8.2 (m, 10), 5.3(s, 2) ppm;

N-(4-chlorophenyl)-2-[((6-(bromomethyl)benzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.4 (s, 1), 10.8 (s, 1), 8.4 (d, 1), 7.4-8.2 (m, 10), 4.9(s, 2) ppm.

C. In a similar manner, other compounds of formula (K) and correspondingintermediates of the compounds of the invention may be prepared.

PREPARATION 6 Compounds of Formula (T)

A. A mixture of 3,3,3-trifluoropropyl bromide (10.0 g, 56.5 mmol),potassium cyanide (5.2 g, 79.8 mmol), tetrabutylammonium iodide (0.1 g,0.3 mmol) and DMSO (10 mL) was heated at 60° C. for 15 hours. Aftercooling, the mixture was extracted with ethyl ether (80 mL) and water(100 mL). The organic layer was washed with water (3×100 mL), dried (Na₂SO₄) and filtered. Ethanol (10 mL) was added, and the solution wascooled to 0° C., and saturated with HCl gas. The vessel was sealed andallowed to stand at ambient temperature for 15 hours. The mixture wasthen added to a solution of hexane (200 mL) and ethyl ether (40 mL). Theprecipitate was collected and dried in vacuo to give 3.2 g of ethyl(2,2,2-trifluoroethyl)acetimidate hydrochloride; NMR (DMSO-d₆ /TFA) 4.4(q, 3), 2.9 (t, 2) 2.6 (m, 2), 1.3 (t, 3) ppm.

B. In a similar manner, other compounds of formula (T) and correspondingintermediates of the compounds of the invention may be prepared.

PREPARATION 7 Compounds of Formula (W)

A. To 2-methoxycarbonyl-3-chloro-4-methylthiophene (100 g, 0.53 mol) indry carbon tetrachloride (1.5 L) were added sulfuryl chloride (65 mL,0.81 mol) and benzoyl peroxide (2.5 g, 10 mmol). The reaction was heatedat reflux for 17 hours, then cooled to ambient temperature andconcentrated of all volatiles in vacuo. Purification of the resultingoil by flash chromatography on silica gel afforded 63 g (54% yield) of2-methoxycarbonyl-3-chloro-4-(chloromethyl)thiophene as a yellow oilwhich crystallized to fine needles upon standing; NMR (CDCl₃) 7.6 (s,1), 4.6 (s, 2), 3.9 (s, 3) ppm.

B. To 2-methoxycarbonyl-3-chloro-4-methylthiophene (0.25 g, 1.3 mmol) indry benzene (25 mL) were added N-bromosuccinimide (0.28 g, 1.6 mmol) andbenzoyl peroxide (0.03 g, 0.13 mmol). The mixture was refluxed whileirradiating with a 250 Watt lamp. After 2 hours the reaction was cooledand concentrated of all volatiles in vacuo. Purification by flashchromatography on silica gel afforded 0.20 g (58% yield) of2-methoxycarbonyl-3-chloro-4-(bromomethyl)thiophene as a white solid;NMR (CDCl₃) 7.6 (s, 1), 4.4 (s, 2), 3.9 (s, 3) ppm.

C. In a similar manner, other compounds of formula (W) and correspondingintermediates of the compounds of the invention may be prepared.

PREPARATION 8 Compounds of Formula (X)

A. To 2-methoxycarbonyl-3-chloro-4-(bromomethyl)thiophene (0.20 g, 0.74mmol) in methylene chloride (7.5 mL) was added 1-methylpiperazine (0.095mL, 0.86 mmol) and the mixture was stirred at ambient temperature. After16 hours, the mixture was poured onto methylene chloride (20 mL) andwashed with dilute aqueous NaHCO₃, water and brine, dried over Na₂ SO₄and concentrated in vacuo. Purification by flash chromatography onsilica gel afforded 0.085 g (40% yield) of2-methoxycarbonyl-3-chloro-4-((4-methylpiperazin-1-yl)methyl)thiopheneas a tan solid; NMR (CDCl₃) 7.4 (s, 1), 3.9 (s, 3), 3.5 (s, 2), 2.3-2.7(br m, 8), 2.2 (s, 3) ppm.

B. In a similar manner, the following compounds were made:

2-methoxycarbonyl-3-chloro-4-((morpholin-4-yl)methyl)thiophene;

2-methoxycarbonyl-3-chloro-4-((thiomorpholin-4-yl)methyl)thiophene.

C. In a similar manner, other compounds of formula (X) and correspondingintermediates of the compounds of the invention may be prepared.

PREPARATION 9 Compounds of Formula (Y)

A. To a solution of 2-methoxycarbonyl-3-chloro-5-methylthiophene (1.3 g,6.8 mmol) in ethanol (16 mL) was added aqueous sodium hydroxide (1 N, 16mL, 16 mmol) and the mixture stirred at ambient temperature. After 3hours the mixture was concentrated of all volatiles in vacuo. Theresidual solid was dissolved in water (60 mL), acidified with 1 N HCland the solid collected by filtration to afford 1.2 g (95% yield) of2-carboxy-3-chloro-5-methylthiophene as a white solid; NMR (CDCl₃) 6.8(s, 1), 2.5 (s, 3) ppm.

B. In a similar manner, the following compounds were made:

2-carboxy-3-methoxybenzo[b]thiophene;

2-carboxy-3-chloro-4-((4-methylpiperazin-1-yl)methyl)thiophene,hydrochloride salt;

2-carboxy-3-chloro-4-cyanothiophene.

C. In a similar manner, other compounds of formula (Y) and correspondingintermediates of the compounds of the invention may be prepared.

PREPARATION 10 Compounds of Formula (FF)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide(4.5 g, 8.0 mmol) in DMF (200 mL) was added cesium carbonate (18 g, 55mmol), followed by epibromohydrin (1.4 mL, 16 mmol). The mixture wasstirred at ambient temperature for 3 days, then filtered. The filtratewas concentrated in vacuo to afford a quantitative yield ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2,3-epoxypropoxy)-5-chlorobenzamide;NMR (CDCl₃) 9.2 (s, 1), 8.8 (s, 1), 8.2 (d, 1), 8.1 (s, 1), 7.7 (d, 1),7.6 (s, 1), 7.3 (s, 1), 7.1 (s, 1), 4.4 (d, 1), 4.3 (s, 2), 4.0 (m, 1),3.4 (br m, 1), 3.0 (br m, 1), 2.9 (s, 3), 2.8 (s, 3), 2.7 (br m, 1) ppm.

B. In a similar manner, the following compound was made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2,3-epoxypropoxy)-5-chlorobenzamide.

C. In a similar manner, other compounds of formula (FF) andcorresponding intermediates of the compounds of the invention may beprepared.

PREPARATION 11 Compounds of Formula (Eb)

A. To N-(5-chloropyridin-2-yl)-2-amino-3-methoxybenzamide (39 g, 140mmol) in benzene (2 L) was added N-chlorosuccinimide (20 g, 148 mmol)and the reaction heated at 50-55° C. After 24 hours the reaction wascooled to ambient temperature and concentrated of all volatiles invacuo. The resulting solid was dissolved in ethyl acetate (1 L), washedwith water (3×100 mL), dried over sodium sulfate, and concentrated.Recrystallization from benzene afforded 40 g (90% yield) ofN-(5-chloropyridin-2-yl)-2-amino-3-methoxy-5-chlorobenzamide asoff-white needles; NMR (CDCl₃) 8.6 (br, 1), 8.3 (m, 2), 7.7 (dd, 1), 7.1(d, 1), 6.8 (d, 1), 5.9 (br, 1), 3.9 (s, 3) ppm.

B. In a similar manner, the following compound was made:

N-(4-chlorophenyl)-2-amino-3-methoxy-5-chlorobenzamide.

C. To a solution of N-(4-chlorophenyl)-2-amino-3-methylbenzamide (0.40g, 1.5 mmol) in chloroform (3 mL) at 0° C. was added SO₂ Cl₂ (0.31 g,2.3 mmol). The mixture was warmed to ambient temperature and stirred for1 hour. Concentration of all volatiles in vacuo affordedN-(4-chlorophenyl)-2-amino-3-methyl-5-chlorobenzamide as a yellow solid;NMR (DMSO-d₆) 10.2 (s, 1), 7.8 (d, 2), 7.6 (s, 1), 7.4 (d, 2), 7.2 (s,1), 6.2 (br, 2), 2.1 (s, 3) ppm.

D. In a similar manner, the following compound was made:

N-(4-chlorophenyl)-2-amino-4-fluoro-5-chlorobenzamide.

E. In a manner similar to those methods described above, other compoundsof formula (Eb) and corresponding intermediates of the compounds of theinvention may be prepared.

PREPARATION 12 Compounds of Formula (Db)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-nitro-3,5-dichlorobenzamide (12 g, 34 mmol)in DMSO (50 mL) was added morpholine (3.6 g, 41 mmol) followed byN,N-diisopropylethylamine (8.9 g, 69 mmol). The mixture was heated at110-120° C. for 4 hours, then cooled to ambient temperature, quenchedwith water (50 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organics were washed with brine (2×30 mL), dried over Na₂ SO₄and concentrated in vacuo. Purification by flash chromatography onsilica gel afforded 6.3 g (46% yield) ofN-(5-chloropyridin-2-yl)-2-nitro-3-(morpholin-4-yl)-5-chlorobenzamide;NMR (CDCl₃) 8.2 (m, 1), 7.7 (m, 1), 7.2-7.4 (m, 3), 3.8 (m, 4), 3.0 (m,4) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-nitro-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 9.8 (br s, 1), 8.4 (d, 1), 8.0 (d, 1), 7.8 (dd, 1),7.6 (d, 2), 3.4 (d, 2), 3.3 (d, 2), 3.2 (m, 4), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-nitro-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide;NMR (DMSO-d₆) 11.5 (br, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.7 (s,1), 7.6 (d, 1), 3.4 (br, 4), 2.9 (m, 4), 1.4 (s, 9) ppm;

N-(4-chlorophenyl)-2-nitro-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-nitro-3-(4-ethylpiperazin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-nitro-3-(4-(ethoxycarbonyl)piperidin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-nitro-3-chloro-5-(N'-methyl-N'-(ethoxycarbonyl)methylamino)benzamide;

N-(5-chloropyridin-2-yl)-2-nitro-3-(N',N'-di(2-methoxyethyl)amino)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-nitro-3-(pyrrolidin-1-yl)-5-chlorobenzamide.

C. Into a solution ofN-(5-chloropyridin-2-yl)-2-nitro-3,5-dichlorobenzamide (4.0 g, 12 mmol)in dimethyl sulfoxide (60 mL) was bubbled an excess of dimethyl aminegas. The mixture was sealed in a pressure tube and heated at 50° C.After 3 hours, the mixture was cooled to ambient temperature, thenpoured into water, and extracted with methylene chloride. The combinedorganic extracts were dried over MgSO₄, and concentrated in vacuo toafford 3.8 g (93% yield) ofN-(5-chloropyridin-2-yl)-2-nitro-3-dimethylamino-5-chlorobenzamide; NMR(CDCl₃) 9.6 (s, 1), 8.2 (d, 1), 7.8 (d, 1), 7.7 (dd, 1), 7.1 (d, 1), 6.9(d, 1), 2.8 (s, 6) ppm.

D. In a similar manner, the following compound was made:

N-(5-chloropyridin-2-yl)-2-nitro-3-amino-5-chlorobenzamide.

E. In a manner similar to those methods described above, other compoundsof formula (Db) and corresponding intermediates of the compounds of theinvention may be prepared.

PREPARATION 13 Compounds of Formula (LL)

A. A mixture of anthranilic acid (10 g, 73 mmol), and phosgene (1.9 Msolution in toluene, 50 mL, 94 mmol) in 1,4-dioxane (120 mL) was stirredat ambient temperature. After 50 hours, the mixture was heated at 65° C.for 10 hours then cooled to ambient temperature. The solid was collectedby filtration, washed with ethyl ether and dried in vacuo to afford 11 g(92% yield) of benzoxazine-2,4-dione as tan solid; NMR (DMSO-d₆) 11.7(s, 1), 7.9 (d, 1), 7.7 (t, 1), 7.2 (t, 1), 7.1 (d, 1) ppm.

B. In a similar manner, the following compounds were made:

6,7-difluorobenzoxazine-2,4-dione; NMR (DMSO-d₆) 11.9 (s, 1), 8.0 (t,1), 7.0 (dd, 1) ppm;

6-fluorobenzoxazine-2,4-dione;

7-fluorobenzoxazine-2,4-dione;

8-methylbenzoxazine-2,4-dione;

7-azabenzoxazine-2,4-dione.

C. In a similar manner, other compounds of formula (LL) andcorresponding intermediates of the compounds of the invention may beprepared.

PREPARATION 14 Compounds of Formula (Ec)2-Amino-(N-4-Chlorophenyl)Benzamide

A. A mixture of benzoxazine-2,4-dione (1.6 g, 10 mmol) and4-chloroaniline (2.5 g, 20 mmol) in 1,4-dioxane (30 mL) was heated atreflux for 15 hours. After cooling the solid was filtered, and thefiltrate was concentrated, washed with ethyl ether. The washing wasconcentrated further to a solid. Additional washing with cold ethylether (10 mL) afforded N-(4-chlorophenyl)-2-aminobenzamide as a tansolid; NMR (DMSO-d₆) 10.1 (s, 1), 7.8 (d, 2), 7.6 (d, 1), 7.4 (d, 2),7.2 (t, 1), 6.8 (d, 1), 6.6 (t, 1), 6.3 (s, 2) ppm.

B. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-amino-4,5-difluorobenzamide; NMR (DMSO-d₆) 10.1 (s,1), 7.8 (m, 3), 7.4 (d, 2), 6.7 (dd, 1), 6.6 (br s, 2) ppm;

N-(4-chlorophenyl)-2-amino-5-fluorobenzamide;

N-(4-chlorophenyl)-2-amino-4-fluorobenzamide;

N-(4-chlorophenyl)-2-amino-3-methylbenzamide; and

N-(4-chlorophenyl)-3-aminopyridin-4-amide.

C. In a similar manner, other compounds of formula (Ec) andcorresponding intermediates of the compounds of the invention may beprepared.

PREPARATION 15 Compound of Formula (OO)

A. To 2-methoxycarbonyl-3-chloro-4-(chloromethyl)thiophene (48 g, 0.21mol) in glacial acetic acid (500 mL) was added sodium acetate (35 g,0.42 mol). The reaction was heated at reflux for 24 hours, then cooledand concentrated in vacuo. The residual oil was made basic by additionof saturated aqueous sodium bicarbonate, and the resulting solutionextracted with ethyl acetate (4×150 mL). The combined extracts weredried over sodium sulfate and concentrated to afford 47 g (90% yield) of2-methoxycarbonyl-3-chloro-4-(acetoxymethyl)thiophene as a light brownoil; NMR (CDCl₃) 7.6 (s, 1), 5.1 (s, 2), 3.9 (s, 3), 2.1 (s, 3) ppm.

B. In a similar manner, other compounds of formula (OO) andcorresponding intermediates of the compounds of the invention may beprepared.

PREPARATION 16 Compounds of Formula (PP)

A. To a solution of2-methoxycarbonyl-3-chloro-4-(acetoxymethyl)thiophene (83 g, 0.33 mol)in 1,4-dioxane (350 mL) was added a solution of sodium hydroxide (26.5g, 0.66 mol) in water (200 mL) and the mixture stirred at ambienttemperature. After 1 hour the dioxane was removed in vacuo and theaqueous solution washed with ethyl acetate (2×1 00 mL). The aqueouslayer was brought to pH 2 by addition of concentrated HCl, thenextracted with n-butanol (4×200 mL). The combined extracts wereconcentrated and the resulting solid dried in vacuo to afford 63 g (90%yield) of 2-carboxy-3-chloro-4-(hydroxymethyl)thiophene as a tan powder;NMR (DMSO-d₆) 7.7 (s, 1), 4.4 (s, 2) ppm.

B. In a similar manner, the following compound was prepared:

2-carboxy-3-chloro-4-(2-(N-methyl-N-tert-butoxycarbonylamino)ethyl)thiophene.

C. In a manner similar to that described above in Paragraph A,2-methoxycarbonyl-3-chloro-4-((morpholin-4-yl)methyl)thiophene (2.0 g,8.2 mmol) was reacted with aqueous sodium hydroxide (1 M, 8.2 mL, 8.2mmol) in 1,4-dioxane (20 mL). Concentration of all volatiles in vacuoafforded 2.0 g (86% yield) of the sodium salt of2-carboxy-3-chloro-4-((morpholin-4-yl)methyl)thiophene; NMR (DMSO-d₆)7.3 (s, 1), 3.5 (m, 4), 3.3 (d, 2), 2.3 (m, 4) ppm.

D. In a similar manner, the following compound was made:

2-carboxy-3-chloro-4-((thiomorpholin-4-yl)methyl)thiophene sodium salt.

E. In a manner similar to that described above, other compounds offormula (PP) and corresponding intermediates of the compounds of theinvention may be prepared.

PREPARATION 17 Compounds of Formula (F)

A. 2-carboxy-3-chloro-4-(hydroxymethyl)thiophene (83 g, 0.43 mmol) wasadded to thionyl chloride (200 mL) and the mixture heated at reflux for4-6 hours. After cooling to ambient temperature, the mixture wasconcentrated of all volatiles in vacuo followed by repeatedconcentration from 1,2-dichloroethane. The residual oil was dissolved inmethylene chloride (250 mL), filtered and concentrated to afford 100 g(89% yield) of 2-chlorocarbonyl-3-chloro-4-(chloromethyl)thidphene as atan waxy solid; NMR (CDCl₃) 7.8 (s, 1), 4.6 (s, 2) ppm.

B. In a similar manner, other compounds of formula (F) and correspondingintermediates of the compounds of the invention may be prepared.

PREPARATION 18 Compounds of Formula (RR)

A. To 5-carboxy-1,3-benzodioxole (50 g, 300 mmol) in trifluoroaceticacid (400 mL) at 0° C. was added HNO₃ (38 mL, 900 mmol) dropwise. Thereaction mixture was stirred at 0° C. for 1 hour, then warmed to ambienttemperature and stirred for 3 hours. The mixture was poured into icewater and the resulting precipitate was collected by filtration. Thesolid was air dried overnight to afford 58 g (92% yield) of5-carboxy-6-nitro-1,3-benzodioxole as a yellow solid; NMR (DMSO-d₆) 7.6(s, 1), 7.3 (s, 1), 6.3 (s, 2) ppm.

B. In a similar manner, other compounds of formula (RR) andcorresponding intermediates of the compounds of the invention may beprepared.

PREPARATION 19

A. To a suspension of 2-carboxy-3-chloro-5-methylthiophene (1.2 g, 6.6mmol) in methylene chloride (16 mL) at 0° C. were added oxalyl chloride(0.6 mL, 7.3 mmol) and a drop of DMF. The mixture was stirred at ambienttemperature for 5 hours, then concentrated of all volatiles and dried invacuo to afford 1.3 g (quantitative yield) of2-chlorocarbonyl-3-chloro-5-methylthiophene as a pale yellow solid; NMR(DMSO-d₆ /TFA) 7.4 (s, 1), 2.5 (s, 3) ppm.

B. In a similar manner, the following compounds were made:

2-chlorocarbonyl-3-methoxybenzo[b]thiophene;

2-chlorocarbonyl-3-chloro-4-cyanothiophene;

2-chlorocarbonyl-3-methyl-5-nitrothiophene;

2-chlorocarbonyl)-3-methyl-4-nitrothiophene; and

2-chlorocarbonyl-3-chloro-4-(2-(N-methyl-N-tert-butoxycarbonylamino)ethyl)thiophene.

C. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 20

A. To a solution of 3,5-dichlorobenzoic acid (50 g, 0.26 mol) insulfuric acid (250 mL) at 0° C. was added nitric acid (18 g, 0.28 mol)dropwise, and the mixture warmed slowly to ambient temperature. After 5hours the mixture was poured onto ice, and the white precipitatecollected by filtration. The solid was washed with water (3×30 mL), anddried in vacuo to afford 55 g (90% yield) of 3,5-dichloro-2-nitrobenzoicacid; NMR (CDCl₃) 8.3 (s, 1), 8.0 (s, 1) ppm.

B. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 21

A. To a solution of (R)-(-)-1-amino-2-propanol (0.40 g, 5.3 mmol) inmethanol (10 mL) at 0° C. were added sodium acetate (0.82 g, 10 mmol)and cyanogen bromide (5 M in acetonitrile, 1 mL, 5.0 mmol). The reactionwas allowed to warm slowly to ambient temperature and stirred for 2hours. The mixture was concentrated in vacuo. A small amount of waterwas added and the solution made basic by addition of a saturated aqueousK₂ CO₃ solution. The mixture was extracted with methylene chloride,dried over K₂ CO₃, and concentrated in vacuo to afford 0.3 g (60% yield)of 2-imino-5(R)-methyloxazolidine; NMR (DMSO-d₆ /TFA) 5.7 (br s, 2), 4.5(m, 1), 3.6 (dd, 1). 3.0 (dd, 1), 1.2 (d, 3) ppm.

B. In a similar manner, the following compounds were made:

2-imino-5(S)-methyloxazolidine; NMR (DMSO-d₆ /TFA) 5.7 (br s, 2), 4.5(m, 1), 3.6 (dd, 1). 3.0 (dd, 1), 1.2 (d, 3) ppm;

2-imino-5-methyloxazolidine; NMR (DMSO-d₆ /TFA) 5.7 (br s, 2), 4.5 (m,1), 3.6 (dd, 1), 3.0 (dd, 1), 1.2 (d, 3) ppm;

2-imino-5,5-dimethyloxazolidine; NMR (DMSO-d₆ /TFA) 3.3 (s, 2), 1.3 (s,6) ppm; and 2-imino-4-methyloxazolidine.

C. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 22

A. To a solution of 1-amino-2-methyl-2-propanol (4.0 g, 45 mmol) in CH₂Cl₂ (25 mL) at 0° C. was added a solution of ethyl isocyanate (3.2 g, 45mmol) in CH₂ Cl₂ (5 mL) dropwise. The mixture was stirred at ambienttemperature for 18 hours, then concentrated of all volatiles in vacuo toafford a quantitative yield of N-(2-methyl-2-hydroxypropyl)-N'-ethylureaas a yellow solid; NMR (DMSO-d₆ /TFA) 5.9 (m. 1), 5.7 (m, 1), 3.0 (m,2), 2.9 (d, 2), 1.0 (s, 6), 0.9 (t, 3) ppm.

B. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 23

A. To a solution of N-(2-methyl-2-hydroxypropyl)-N'-ethylurea (7.2 g, 45mmol) in CH₂ Cl₂ (100 mL) at 0° C. was added a solution of thionylchloride (5.4 g, 45 mmol) in CH₂ Cl₂ (20 mL). The mixture was warmed toambient temperature. After 2 hours, the mixture was concentrated invacuo, and the resulting solid triturated with boiling water. Themixture was cooled to ambient temperature and made basic by addition ofsaturated aqueous K₂ CO₃. The mixture was extracted with methylenechloride, dried over K₂ CO₃, and concentrated in vacuo to afford 3.2 g(50% yield) of 2-ethylamino-5,5-dimethyloxazoline; NMR (DMSO-d₆ /TFA)3.2 (s, 2), 3.0 (q, 2), 1.3 (s, 6), 1.0 (t, 3) ppm.

B. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 24

A. To a solution of 1-amino-2-propanol (2.0 g, 27 mmol) intetrahydrofuran (20 mL) was added a solution of thiocarbonyldiimidazole(5.3 g, 27 mmol) in tetrahydrofuran (5 mL). The mixture was stirred atambient temperature for 3 hours, then concentrated in vacuo.Purification by flash chromatography on silica gel afforded 2.9 g (93%yield) of 5-methyl-2-thioxooxazolidine; NMR (CDCl₃) 8.4 (br s, 1), 5.0(m, 1), 3.8 (t, 1). 3.4 (t, 1), 1.5 (d, 3) ppm;

B. In a similar manner, the following compound was made:

4-methyl-2-thioxooxazolidine.

C. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 25

A. To a solution of 5-methyl-2-thioxooxazolidine (2.7 g, 23 mmol) inPOCl₃ (40 mL) was added PCl₅ (4.8 g, 23 mmol). The mixture was heated at100° C. for 3 hours, then cooled to ambient temperature and concentratedin vacuo. The resulting yellow oil was dissolved in methylene chloride,filtered through silica gel and concentrated to afford a quantitativeyield of 2-chloro-5-methyl-2-oxazoline.

B. In a similar manner, the following compound was made:

2-chloro-4-methyl-2-oxazoline.

C. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 26

A. To a solution of 2-carboxy-3-chlorothiophene (2.0 g, 12.3 mmol) inchloromethyl methyl ether (10 mL) was added TiCl₄ (4.0 mL, 6.9 g, 36mmol) at 0° C. under N₂. The resulting dark orange suspension was warmedto ambient temperature. After 5 hours the reaction mixture was pouredonto methylene chloride (75 mL) and ice water (100 mL) with vigorousstirring. The layers were separated and the aqueous layer was extractedwith ethyl acetate (100 mL) and the combined organics extracted with 3portions of aqueous NaHCO₃ (100 mL, 25-50% saturated). The combinedaqueous extracts were made acidic by addition of concentrated HCl andthe resulting precipitate extracted into ethyl acetate (3×100 mL). Thecombined organic extracts were dried over MgSO₄ and concentrated of allvolatiles in vacuo. The resulting solid was dissolved in acetonitrile,water and trifluoroacetic acid and purified by HPLC on a C18 Dynamaxcolumn with 30-55% acetonitrile in water gradient with 0.1%trifluoroacetic acid to afford 0.83 g (26% yield) of2-carboxy-3-chloro-4,5-di(chloromethyl)thiophene as a white solid: NMR(CDCl₃) 4.8 (s, 2), 4.6 (s, 2) ppm.

B. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 27

A.N-(5-Chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.054 g, 0.11 mmol) and 1,1-di(methylthio)-2-nitroethene (0.092 g, 0.56mmol) were dissolved in DMF (1 mL) and stirred at 50,° C. under nitrogenfor 16 hours. The reaction mixture was then partitioned between water(25 mL) and ethyl acetate (60 mL), the layers were separated and theaqueous layer extracted with ethyl acetate (30 mL). The combined organiclayers were washed with water (3×30 mL), brine (30 mL), dried overmagnesium sulfate, concentrated in vacuo, and dried under vacuum. Thecrude product was purified by flash chromatography on silica gel,eluting with 70% ethyl acetate/hexanes to giveN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-nitro-1-methylthioethenyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamideas a yellow foam.

B. In a similar manner, the following compound was made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylthio(cyanoimino)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

C. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 28

A.N-(5-Chloropyridin-2-yl)-2-[((4-(2-amino-2-(hydroxyimino)ethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(3.06 g, 5.8 mmol) was dissolved in trichloroacetic acid (3.8 g, 23mmol) and the mixture heated to 85° C. Trichloroacetyl chloride (1.3 mL,11.6 mmol) was added, and the temperature was increased to 94° C. Afterone hour the reaction mixture was allowed to cool to room temperature,diluted with water (150 mL) and a small amount of ethyl acetate, andadjusted to basic pH with 1 N NaOH. The aqueous layer was extracted withethyl acetate (300 mL). The organic phase was washed with 1 M sodiumbicarbonate (150 mL), dried over magnesium sulfate, concentrated invacuo, and dried under vacuum. The crude product was purified by flashchromatography on silica gel eluting with 25% ethyl acetate/hexanes toaffordN-(5-chloropyridin-2-yl)-2-[((4-((5-trichloromethyl-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

B. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 29

A. To a solution of 2-carboxy-3-methylthiophene (10 g, 70.3 mmol) in 80mL of trifluoroacetic acid at 0° C. was added HNO₃ (1.2 mL, 1.0 eq.)dropwise. The reaction mixture was warmed to ambient temperature andafter 4 hours another 1.0 eq. of HNO₃ was added. The reaction mixturewas made basic with aqueous sodium bicarbonate and washed with ethylacetate. The aqueous layer was acidified with concentrated HCl andextracted with ethyl acetate. The organic layer was dried over sodiumsulfate and concentrated in vacuo to afford 5.75 g (53%) of2-carboxy-3-methyl-5-nitrothiophene and2-carboxy-3-methyl-4-nitrothiophene, as a yellow solid.

B. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 30

A. N-tert-Butoxycarbonylpiperazine (2.94 g, 16.0 mmol) was dissolved inpyridine (8 mL) under nitrogen and the solution cooled to 0° C.Methanesulfonyl chloride (1.5 mL, 19.3 mmol) was added. After 5 minutes,more pyridine was added (5 mL) and the reaction mixture was allowed towarm to ambient temperature. After 40 minutes, the pyridine was removedin vacuo. The residue was dissolved in ethyl acetate (250 mL), washedwith 0.1M citric acid (3×125 mL), dried over magnesium sulfate,concentrated in vacuo, and dried under vacuum to give 3.84 g (92%) ofN-tert-butoxycarbonyl-N'-methylsulfonylpiperazine.

B. N-tert-butoxycarbonyl-N'-methylsulfonylpiperazine (3.84 g, 14.5 mmol)was suspended in methylene chloride (100 mL) under nitrogen andtrifluoroacetic acid (10 mL) was added. After 3 hours, the reactionmixture was concentrated in vacuo and the residue dissolved in water(150 mL). The aqueous layer was washed with ether (2×75 mL). The pH ofthe aqueous layer was then adjusted to 10 and it was extracted withmethylene chloride (3×120 mL). The methylene chloride layers were driedover magnesium sulfate, and concentrated in vacuo to give 0.99 g ofN-methylsulfonylpiperazine. Further extraction of the aqueous layer with10% methanol/methylene chloride (3×120 mL) afforded 0.44 g ofN-methylsulfonylpiperazine, for a total of 1.43 g (59%).

C. In a similar manner, other corresponding intermediates of thecompounds of the invention may be prepared.

PREPARATION 31

A. Hydroxylamine hydrochloride (6.12 g, 88 mmol) was added to a solutionof sodium methoxide prepared by dissolving sodium (2.02 g) in methanol(25 mL). Additional methanol (50 mL) was added, followed by(methylthio)acetonitrile (6.0 mL, 71.5 mmol). The reaction mixture wasrefluxed for 5 hours, filtered while hot, concentrated in vacuo, anddried under vacuum to give 1-amino-1-hydroxyimino-2-methylthioethane inquantitative yield.

B. In a similar manner, 1-amino-1-hydroxyimino-2-methoxyethane wasprepared.

C. 1-Amino-1-hydroxyimino-2-methylthioethane (11.32 g, 94.2 mmol) wassuspended in dry chloroform (60 mL) under nitrogen. A solution ofchloroacetyl chloride (7.5 mL, 94.2 mmol) in chloroform (20 mL) wasadded dropwise. After stirring for 1 hour, a solution of triethylamine(15.8 mL, 113 mmol) in chloroform (20 mL) was added dropwise. Thereaction mixture was stirred for 15 minutes, then washed with water(2×70 mL), dried over sodium sulfate, concentrated in vacuo, and driedunder vacuum to yield 11.4 g (62% yield) of1-amino-1-((chloromethyl)carbonyloxy)imino-2-methylthioethane, as abrown semi-solid.

D. In a similar manner,1-amino-1-((chloromethyl)carbonyloxy)imino-2-methoxyethane was prepared.

E. 1-Amino-1-((chloromethyl)carbonyloxy)imino-2-methylthioethane (3.04g, 15.5 mmol) was dissolved in xylenes (15 mL) under nitrogen. Thereaction mixture was refluxed for 3 hours, concentrated in vacuo, anddried under vacuum. The crude product was purified by flashchromatography on silica eluting with 10% ethyl acetate/hexanes to give1.14 g (41% yield) of5-chloromethyl-3-methylthiomethyl-1,2,4-oxadiazole.

F. In a similar manner,5-chloromethyl-3-methylthiomethyl-1,2,4-oxadiazole was prepared.

G. In a manner similar to those methods described above, othercorresponding intermediates of the compounds of the invention may beprepared.

PREPARATION 32

A. Acetic anhydride (30.91 g, 0.303 mol) was cooled to 0° C. and formicacid (20.6 g, 0.394 mol) was added dropwise. After stirring for 30minutes at 0° C., the reaction mixture was warmed to room temperaturethen heated to 50° C. The reaction mixture was stirred for 5 hours, thencooled to ambient temperature. The product, acetic formic anhydride, wasused in the next step without further purification.

B. To a solution of acetic formic anhydride (26.7 g, 0.303 mol) in THF(100 mL) was added 2-aminoimidazole (25.2 g, 0.303 mol) in THF (200 mL)at ambient temperature. After stirring for 16 hours, the reactionmixture was concentrated and the resulting solid was suspended inmethylene chloride. NH₃ (g) was bubbled into the suspension and thereaction mixture was concentrated. The resulting white slurry was loadedonto a silica column and eluted with 0-10% methanol in methylenechloride gradient to afford 25.9 g of 2-(formylamino)imidazole as awhite solid.

C. In a similar manner the following compound was prepared:

2-(acetylamino)imidazole.

D. To a suspension of 2-(formylamino)imidazole (25.9 g, 0.233 mol) inTHF (200 mL) was added BH₃ -THF (900 mL of a 1 M solution in THF, 0.9mol) at ambient temperature. The resulting white turbid solution wasstirred at ambient temperature for 16 hours. The reaction was quenchedwith methanol and adjusted to pH 2 with 3 N HCl in ethyl acetate. Thesolution was heated to reflux for an hour and then was concentrated. Theresulting solid was dissolved in THF and NH₃ (g) was bubbled into thesolution. The resulting white solid was removed by filtration and thefiltrate was concentrated to afford 2-(methylamino)imidazole as a darkoil.

E. In a similar manner the following compound was prepared:

2-(ethylamino)imidazole.

F. In a manner similar to those methods described above, othercorresponding intermediates of the compounds of the invention may beprepared.

PREPARATION 33

A. To a solution of 2-methoxycarbonyl-3-chloro-4-hydroxymethylthiophene(6 g, 29 mmol) in methylene chloride (100 mL) were added triethylamine(8.1 mL, 58 mmol) and methanesulfonyl chloride (2.5 mL, 32 mmol) atambient temperature. After stirring for 6 hours, the reaction mixturewas concentrated to afford2-methoxycarbonyl-3-chloro-4-(methylsulfonyloxy)methylthiophene. Thecrude product was dissolved in DMF (150 mL) and excess potassium cyanidewas added to the solution. The reaction mixture was stirred at ambienttemperature for 16 hours, then poured into water, and extracted withmethylene chloride. The combined extracts were dried over Na₂ SO₄,filtered, and concentrated in vacuo to afford2-methoxycarbonyl-3-chloro-4-cyanomethylthiophene.

B. 2-Methoxycarbonyl-3-chloro-4-cyanomethylthiophene (2 g, 9.27 mmol)was dissolved in THF (100 mL) and BH₃ -THF (18.6 mL of a 1 M solution inTHF, 18.6 mmol) was added. After stirring for 16 hours at ambienttemperature, the reaction was quenched with water followed by 1 M NaOH.Potassium carbonate was added to afford two layers. The organic layerwas separated and concentrated in vacuo to afford2-methoxycarbonyl-3-chloro-4-(2-aminoethyl)thiophene.

C. 2-Methoxycarbonyl-3-chloro-4-(2-aminoethyl)thiophene was dissolved inTHF (50 mL), and di-tert-butyl dicarbonate (2.23 g, 10.2 mmol) was addedat ambient temperature. After 1 hour, water was added, and the reactionmixture was extracted with methylene chloride. The combined extractswere dried over Na₂ SO₄, filtered, concentrated in vacuo, and purifiedby flash chromatography on gel to afford 1.42 g of2-methoxycarbonyl-3-chloro-4-(2-(tert-butoxycarbonylamino)-ethyl)thiophene.

D. To a solution of2-methoxycarbonyl-3-chloro-4-(2-(N-methyl-N-tert-butoxycarbonylamino)ethyl)-thiophene(0.93 g, 2.91 mmol) in DMF (10 mL) were added NaH (0.23 g, 5.82 mmol)and iodomethane (0.36 mL, 5.82 mmol) at ambient temperature. Afterstirring for 48 hours, water was added, and the reaction mixture wasextracted with methylene chloride. The combined extracts were dried overNa₂ SO₄, filtered, concentrated in vacuo, and purified by flashchromatography on silica to afford2-methoxycarbonyl-3-chloro-4-(2-(N-methyl-N-tert-butoxycarbonylamino)ethyl)thiophene(0.45 g).

E. In a manner similar to those methods described above, othercorresponding intermediates of the compounds of the invention may beprepared.

PREPARATION 34

A. To a solution of 2-chloro-3-nitropyridine (5 g, 31.6 mmol, 1.0 eq.)in 50 mL of DMF was added copper cyanide (2.47 g, 38 mmol, 1.2 eq.) andthe reaction heated to 100° C. for 16 hours. The reaction mixture wascooled to ambient temperature and poured into 100 mL of water. Themixture was extracted with ethyl acetate (3×50 mL) and the combinedethyl acetate portions were dried over soduim sulfate and concentrated.The crude material was chromatographed on silica with 3:7 ethylacetate/hexanes to give 2-cyano-3-nitropyridine as a yellow solid.

B. To a solution of 2-cyano-3-nitropyridine (0.5 g, 3.4 mmol, 1 eq.) in50 mL of ethanol was added HCl gas. The reaction was stirred at ambienttemperature for 16 hours and concentrated. The residue was dissolved in50 mL of water and the solution neutralized with saturated aqueoussodium bicarbonate and extracted with ethyl actetate (3×50 mL). Thecombined ethyl acetate extractions were dried over sodium sulfate andconcentrated. The residue was chromatographed to give2-ethoxycarbonyl-3-nitropyridine (0.5 g, 90% yield) as a pale yellowoil.

C. To a solution of 2-ethoxycarbonyl-3-nitropyridine (0.5 g, 2.5 mmoL, 1eq.) in 20 mL of methanol and 5 mL of water was added lithium hydroxide(0.2 g, 4.5 mmoL, 1.8 eq.) and the mixture stirred for 16 hours atambient temperature. The reaction was concentrated and 50 mL of 1N KOHwas were added. The solution was washed with 25 mL of ethyl actetate,acidified with 1 N HCl, and extracted with ethyl acetate (3×50 mL). Thecombined ethyl acetate extractions were dried over sodium sulfate andconcentrated to give 2-carboxy-3-nitropyridine as a yellow solid (0.4 g,95% yield).

D. In a manner similar to those methods described above, otherintermediates for compounds of the invention where the B ring is aheterocyclic may be prepared.

EXAMPLE 1 Compounds of Formula (Ia)

A. To a solution ofN-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.1 mmol) in DMF (40 mL) at 0° C. was added 1-methylpiperazine(1.2 mL, 1.1 g, 11 mmol), and the mixture stirred for 0.5 hours at 0°C., then warmed to ambient temperature. After 7 hours the reactionmixture was poured into water (150 mL) and the resulting solid collectedby filtration, washed with water (50 mL) and acetonitrile (10 mL).Purification by flash chromatography on silica gel afforded 0.77 g (64%yield) ofN-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white foam: NMR (DMSO-d₆ /TFA) 10.4 (s, 1), 9.4 (s, 1), 7.2-8.1 (m,7), 4.4 (s, 2), 3.8 (s, 3), 3.0-3.8 (br m, 8), 2.8 (s, 3) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.7 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1(s, 1), 7.8 (dd, 1), 7.7 (d, 1), 7.5 (d, 1), 4.4 (s, 2), 3.6-3.3 (br m,8), 2.9 (s, 6), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.7 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1(d, 1), 7.8 (dd, 1), 7.6 (d, 1), 7.5 (d, 1), 4.4-4.3 (br m, 2), 3.2-3.0(br m, 4), 2.9 (s, 6), 2.8 (d, 6), 2.7 (s, 3), 2.3 (br s, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.7 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1(d, 1), 7.8 (dd, 1), 7.6 (d, 1), 7.4 (d, 1), 4.4 (br s, 2), 3.5 (br s,4), 2.9 (s, 12), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.7 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1(d, 1), 7.9 (dd, 1), 7.7 (d, 1), 7.5 (d, 1), 4.5-4.3 (br m, 2), 3.65-3.5(br m, 3), 3.1-3.0 (br m, 2), 2.9 (s, 6), 2.8 (s, 3), 2.7 (s, 3),2.4-2.3 (br m, 2), 2.1-1.9 (br m, 2) ppm;

N-(pyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 8.5 (d, 1), 8.3 (t, 1), 8.2 (s, 1), 8.1(d, 1), 7.9 (s, 1), 7.8 (d, 1), 7.6 (d, 1), 7.5 (t, 1), 4.4 (s, 2),3.6-3.2 (br m, 8), 2.9 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-(3-(imidazol-1-yl)propyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1), 9.1 (s, 1), 8.4 (d, 1), 8.2(s, 1), 7.9 (d, 1), 7.8-7.6 (m, 5), 7.4 (d, 2), 4.3 (t, 2), 4.2 (br s,2), 3.0 (br s, 2), 2.2 (m, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-(2-(morpholin-4-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 7.4-8.5 (m, 7), 3.3-3.7 (m, 8), 2.4-2.7 (m, 6) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-(morpholin-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 7.4-8.6 (m, 7), 3.6 (s, 2), 3.0-3.7 (m, 8), 2.2-2.7(m, 6) ppm; /TFA)

N-(5-chloropyridin-2-yl)-2-[((4-((4-hydroxypiperidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1), 9.4 (s, 1), 8.3 (s, 1), 8.2(d, 1), 8.1 (s, 1), 7.8 (d, 1), 7.4 (s, 1), 7.3 (s, 1), 4.3 (m, 2), 3.9(s, 3), 3.8 (br s, 1), 3.4 (m, 1), 3.2 (m, 2), 3.0 (m, 1), 1.8 (m, 4)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1), 10.1 (br s, 1), 8.4 (d, 1),8.3 (s, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (d, 1), 7.4 (d, 2), 4.4 (s, 2),3.6 (m, 2), 3.4 (br s, 6), 2.8 (s, 3), 2.0 (br s, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (br s, 1), 9.4 (s, 1), 8.3 (s, 1),8.2 (m, 1), 8.1 (d, 1), 7.9 (d, 1), 7.4 (s, 1), 7.3 (s, 1), 4.4 (m, 2),4.0 (m, 1), 3.9 (s, 3), 3.4 (m, 2), 3.1 (m, 2), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1), 9.4 (br s, 1), 8.4 (s, 1),8.2 (s, 1), 8.1 (d, 1), 7.9 (d, 1), 7.4 (s, 1), 7.3 (s, 1), 4.4 (br s,2), 3.9 (s, 3), 3.8 (m, 2), 3.2 (m, 4), 1.3 (m, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1), 10.0 (br s, 1), 8.4 (d, 1),8.3 (s, 1), 8.0 (s, 1), 7.8 (d, 2), 7.7 (d, 1), 7.4 (d, 2), 4.4 (s, 2),3.6 (m, 4), 3.3 (br s, 2), 2.8 (s, 3), 2.0 (br s, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolidin-1-yl)-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1), 9.4 (s, 1), 8.4 (s, 1), 8.2 (d, 1), 8.1 (s,1), 7.9 (d, 1), 7.0 (s, 1), 6.9 (s, 1) 4.3 (s, 2), 3.5 (br s, 4), 3.4(br s, 8), 2.9 (s, 3), 1.9 (br s, 4) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (CDCl₃) 11.1 (s, 1), 8.7 (s, 1), 8.3 (d, 1), 7.7 (d, 2), 7.5 (s, 2),7.4 (d, 2), 7.3 (dd, 1), 3.7 (t, 2), 3.6 (s, 2), 2.7 (t, 2), 2.3 (s, 3)ppm;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.8 (s,1), 7.7 (d, 2), 7.6 (d, 1), 7.4 (d, 2), 3.4 (s, 2), 2.4 (m, 4), 2.3 (m,4), 2.1 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2-dimethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s,1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 3.5 (s, 2), 2.5 (d, 2), 2.3 (d,2), 2.2 (s, 3), 2.1 (s, 6) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(ethoxycarbonylmethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (CDCl₃) 11.1 (s, 1), 8.6 (s, 1), 8.3 (d, 1), 7.7 (d, 2), 7.6 (s, 1),7.5 (d, 1), 7.4 (d, 2), 7.3 (dd, 1), 4.2 (q, 2), 3.7 (s, 2), 3.3 (s, 2),2.5 (s, 3), 1.3 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.7 (s, 1), 7.4 (d,1), 7.2 (d, 1), 3.9 (s, 3), 3.4 (s, 2), 2.4 (t, 2), 2.2 (t, 2), 2.1 (s,3), 2.0 (s, 6), 1.5 (m, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.3 (s, 1), 8.4 (s, 1), 8.1 (d, 1), 7.9(d, 1), 7.7 (s, 1), 7.4 (s, 1), 7.2 (s, 1), 3.9 (s, 3), 3.4 (s, 2), 3.3(s, 3), 2.2-2.5 (br m, 11), 1.0 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.9 (s, 1), 9.4 (s, 1), 8.4 (s, 1), 8.1(d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.4 (s, 1), 7.2 (s, 1), 4.4 (t, 1), 3.9(s, 3), 3.5 (m, 4), 3.3 (d, 2), 2.4 (m, 3) ppm;

5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole,NMR (DMSO-d₆ /TFA) 11.5 (s, 1), 11.0 (s, 1), 9.6 (s, 1), 7.5-8.4 (m, 6),6.1 (s, 2), 4.4 (m, 2), 3.8 (t, 2), 3.2 (m, 2), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (br s, 1), 9.3 (br s, 1), 8.3 (s, 1), 8.1 (d, 1), 7.9(d, 1), 7.8 (s, 1), 7.2 (s, 1), 7.1 (s, 1), 3.6 (m, 1), 3.5 (br s, 2),3.3 (m, 2), 2.5 (m, 1), 2.3 (m, 1), 2.2 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(((t-butyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (br, 1), 9.4 (br, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9(dd, 1), 7.7 (s, 1), 7.4 (s, 1), 7.2 (s, 1), 3.9 (s, 3), 3.6 (s, 2), 1.1(s, 9) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(((2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((4-hydroxycyclohexyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-(((2-methoxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole;

N-(5-chloropyridin-2-yl)-2-[((4-(((2-methoxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.8 (s, 1), 9.5 (br s, 1), 9.4 (s, 1), 8.2 (d, 1),8.1 (s, 1), 8.0 (d, 1), 7.8 (dd, 1), 7.1 (s, 2), 4.3 (br d, 2), 3.75 (t,2), 3.15 (br m, 4), 1.2 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3,4,5-trimethoxybenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(ethylamino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.90 (s, 1H), 9.40 (s, 1H), 8.80 (br s, 2H), 8.75 (d,1H), 8.20 (d, 1H), 8.10 (s, 1H), 7.80 (dd, 1H), 7.48 (d, 1H), 7.60 (d,1H), 4.15 (s, 2H), 3.85 (s, 3H), 3.05 (br s, 2H), 1.20 (t, 3H) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.90 (s, 1H), 9.38 (s, 1H), 8.30 (d, 1H), 8.20 (d, 1H),7.90 (dd, 1H), 7.70 (s, 1H), 7.40 (d, 1H), 7.25 (d, 1H), 3.90 (s, 3H),3.30 (s, 2H), 2.40 (q, 2H), 2.10 (s, 3H), 1.00 (t, 3H) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-formylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1), 9.4 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 8.0 (s,1), 7.9 (dd, 1), 7.8 (s, 1), 7.4 (d, 1), 7.2 (d, 1), 3.9 (s, 3), 3.5 (s,2), 3.3 (s, 4), 2.4 (m, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((pyrrolidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (CDCl₃) 9.1 (s, 1), 8.8 (s, 1), 8.3 (d, 1), 8.2 (d, 1), 7.7 (dd, 1),7.5 (s, 1), 7.3 (d, 1), 7.1 (d, 1) 3.9 (s, 3), 3.6 (s, 2), 2.6 (m, 4),1.8 (m, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(1-methylethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 12.4 (s, 1), 10.9 (s, 1), 9.4 (s, 1), 8.3 (d, 1), 8.1(d, 1), 7.9 (dd, 1), 7.8 (d, 2), 7.6 (s, 1), 7.3 (dd, 2), 7.0 (br d, 2),5.1 (s, 2), 3.9 (s, 3), 3.8 (m, 1), 1.2 (d, 6) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((morpholin-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (CDCl₃) 9.1 (s, 1), 8.7 (s, 1), 8.2 (d, 1), 8.1 (s, 1), 7.6 (dd, 1),7.4 (s, 1), 7.2 (d, 1), 7.0 (s, 1), 3.9 (s, 3), 3.7 (bs, 4), 3.5 (s, 2),2.5 (bs, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-methylethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (CDCL₃) 9.1 (s, 1), 8.9 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.6 (dd, 1),7.4 (s, 1), 7.3 (s, 1), 7.05 (s, 1), 3.9 (s, 3), 3.8 (s, 2), 2.9 (m, 1),1.0 (d, 6) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(diethylamino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1), 9.4 (s, 1), 8.4 (s, 1), 8.2(s, 1), 8.1 (d, 1), 7.9 (d, 1), 7.3 (s, 1), 7.2 (s, 1), 4.2 (s, 2), 3.8(s, 3), 3.1 (bs, 4), 1.2 (m, 6) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (br s, 1), 9.4 (s, 1), 9.2 (br s,1), 8.3 (d, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8 (dd, 1), 7.2 (d, 2), 4.8 (t,1), 4.6 (dd, 2), 4.3 (t, 1), 4.1 (m, 1), 3.8 (s, 3), 1.2 (d, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-(methylsulfonyl)piperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1), 9.4 (s, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd,1), 7.8 (s, 1), 7.4 (d, 1), 7.2 (d, 1), 3.9 (s, 3), 3.5 (s, 2), 3.1 (s,4), 2.9 (s, 3), 2.5 (s, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(((2(S),3(S)-3-hydroxybut-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((2(R),3(S)-3-hydroxybut-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((aminocarbonylmethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-(((3-aminopropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(N"-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolin-1-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((di(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

C. In a manner similar to Paragraph A above,N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(2.0 g, 4.0 mmol) was reacted with 2-aminoimidazole (1.3 g, 16 mmol) togiveN-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,which was purified by HPLC on a C18 Vydac column with acetonitrile inwater gradient with 0.1% trifluoroacetic acid to affordN-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 10.4 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (br, 1), 7.6(s, 1), 4 (d, 1), 7.3 (d, 1), 6.9 (dt, 1), 5.0 (s, 2), 4.8 (s, 3) ppm.

D. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(S)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (d, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8 (dd, 1), 7.4 (s, 1), 7.3 (s, 1),5.1 (m, 1), 4.6 (q, 2), 3.9 (s, 3), 3.9 (d, 1), 3.4 (t, 1), 1.4 (d, 3)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(((thiazol-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.7 (s, 1), 7.4 (d, 1), 7.4 (d, 1),7.3 (d, 1), 7.1 (d, 1), 5.2 (s, 2), 3.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.5 (s, 1),8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.5 (d, 2), 3.6 (s, 2),3.5 (br m, 2), 3.4 (br m, 4), 3.2-2.8 (br m, 8), 2.8 (s, 3), 2.7 (s, 3),2.6-2.4 (br m, 2) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2-diethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1), 8.3 (m, 2), 8.0 (s, 1), 7.7(m, 3), 7.4 (d, 2), 4.4 (s, 2), 3.5 (m, 3), 3.2 (q, 4), 2.8 (s, 3), 1.2(t, 6) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.6 (s, 1),8.4 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.4 (d, 2), 4.4 (br d,2), 3.8 (t, 2), 3.5 (m, 2), 3.3 (m, 2), 3.2 (m, 2), 3.1 (d, 4), 2.8 (s,3), 2.7 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (d, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8 (dd, 1), 7.4 (s, 1), 7.3 (s, 1),5.1 (m, 1), 4.6 (q, 2), 3.9 (s, 3), 3.9 (d, 1), 3.4 (t, 1), 1.4 (d, 3)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5,5-(dimethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (d, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8 (dd, 1), 7.4 (s, 1), 7.3 (s, 1),4.6 (s, 2), 3.8 (s, 3), 3.5 (s, 2), 1.5 (s, 6) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-ethylimino-5,5-(dimethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (d, 1), 8.1 (d, 1), 7.9 (s, 1), 7.8 (dd, 1), 7.3 (s, 1), 7.2 (s, 1),4.6 (s, 2), 3.8 (s, 3), 3.5 (s, 2), 3.3 (q, 2), 1.4 (s, 6), 1.1 (t, 3)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(R)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d6/TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (d, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8 (dd, 1), 7.4 (s, 1), 7.3 (s, 1),5.1 (m, 1), 4.6 (q, 2), 3.9 (s, 3), 3.9 (d, 1), 3.4 (t, 1), 1.4 (d, 3)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),7.3-8.5 (m, 6), 3.9 (s, 2), 3.7 (br d, 4), 3.0-3.7 (m, 8), 2.9 (br d,2), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),7.3-8.4 (m, 6), 4.1 (br d, 2), 2.6-3.8 (m, 14) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),7.3-8.5 (m, 6), 4.1 (br d, 2), 2.8-3.8 (m, 14) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(N'-methyl-N'-(2-(dimethylamino)ethyl)amino)-3-chlorothiophen-2-yl)carbonyl)amino]-3-chloro-5-(N'-methyl-N'-(ethoxycarbonyl)methylamino)benzamide;trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),6.9-8.4 (m, 6), 5.6 (s, 2), 4.4 (s, 2), 4.3 (s, 2), 4.1 (q, 2), 3.5 (brd, 4), 3.0 (s, 3), 2.8 (s, 3), 2.7 (s, 3), 1.2 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),7.3-8.5 (m, 6), 4.2 4.5 (m, 2), 3.6-3.9 (m, 6), 3.1-3.3 (m, 2), 2.9 (brd, 2), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1),7.3-8.5 (m, 6), 3.0-4.2 (m, 14), 2.9 (s, 3), 2.5 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(morpholin-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11 (s, 1), 9.6 (s, 1),7.3-8.5 (m, 6), 4.1 (br d, 2), 3.8 (br d, 4), 3.7 (br d, 4), 3.0-3.4 (m,8), 2.9 (br d, 4), 2.5 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amnino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1),7.3-8.5 (m, 6), 2.9-3.7 (m, 14), 2.4 (m, 4), 2.1 (s, 3), 2.2 (s, 6), 1.6(m, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11 (s, 1), 9.6 (s, 1),7.3-8.5 (m, 6), 2.8-4.2 (m, 14), 2.5 (s, 3), 1.8-2.0 (m, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-methoxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),7.3-8.5 (m, 6), 4.2-4.6 (m, 2), 3.6-3.8 (m, 6), 3.3 (s, 3H, 2.6-2.8 (m,4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),7.3-8.5 (m, 6), 2.9-3.9 (m, 18), 2.5 (s, 3), 1.2 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N',N'-di(2-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),7.2-8.5 (m, 6), 4.0-4.6 (m, 4), 3.1-3.4 (m, 4), 1.1 (s, 3), 1.2 (s, 3)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (br d, 1), 9.6 (br d,1), 7.2-8.5 (m, 6), 4.2-4.5 (m, 4), 3.9 (s, 3), 3.0-3.4 (m, 2), 2.7 (s,3), 2.2 (m, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-methylethyl)-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (d, 1), 9.6 (d, 1),7.3-8.5 (m, 6), 4.7 (m, 2), 3.3-3.8 (m, 13), 2.9 (s, 3), 2.1 (m, 4), 1.3(m, 6) ppm;

N-(4-chlorophenyl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.5 (s, 1), 9.7 (s, 1),7.2-8.3 (m, 7), 4.2-4.5 (m, 2), 3-3.9 (m, 8), 2.9 (br d, 4), 2.8 (s, 3)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2,2-dimethyl-2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),7.2-8.5 (m, 6), 4.2-4.6 (m, 2), 3.9 (s, 3), 3.0-3.3 (m, 2), 2.9 (s, 3),1.3 (s, 3), 1.2 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(ethoxycarbonyl)piperidin-1-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1),7.3-8.5 (m, 6), 4.2-4.5 (m, 2), 4.0 (q, 2), 3.7 (t, 2), 3.0-3.5 (m, 4),2.6-2.9 (m, 5), 1.6-2.0 (m, 4), 1.1 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),7.3-8.5 (m, 6), 3.8-4.4 (m, 3), 3.7 (s, 3), 2.7-3.5 (m, 11) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(di(2-methoxyethyl)amino)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.7 (s, 1),7.3-8.4 (m, 6), 4.2-4.5 (m, 2), 3.7 (t, 2), 3.2-3.4 (m, 10), 3.1 (s, 6)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.8 (br, 1),9.4 (s, 1), 8.4 (s, 1), 8.2 (s, 1), 8.2 (d, 1), 7.9 (dd, 1), 4.4 (dd,2), 3.6 (br, 2), 3.1 (br, 2), 2.9 (s, 3), 2.8 (s, 3), 2.4 (br, 2), 2.0(q, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (s, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.2 (2s, 2), 4.4 (s,2), 3.6 (s, 4), 2.9 (s, 6), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (br, 1),9.4 (s, 1), 8.4 (s, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 4.4 (d, 1),4.3 (d, 1), 3.8 (t, 2), 3.2 (br, 2), 2.8 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-fluorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 10.7 (s, 1),8.3 (dd, 1), 7.9 (s, 1), 7.8 (m, 1), 7.7 (d, 2), 7.5 (m, 1), 7.4 (d, 2),3.6 (s, 2), 3.4 (br, 2), 3.0 (br, 6), 2.8 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((((2-hydroxyethoxy)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1),9.0 (br s, 2), 8.3 (d, 1), 8.2 (s, 1), 8.0 (s, 1), 7.8 (d, 2), 7.7 (d,1), 7.4 (d, 2), 4.2 (s, 2), 3.7 (m, 2), 3.5 (m, 4), 3.2 (br s, 2) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1),8.4 (d, 1), 8.3 (s, 1), 8.0 (s, 1), 7.8 (d, 2), 7.6 (d, 1), 7.4 (d, 2),4.4 (s, 2), 3.8 (br s, 2), 3.5 (m, 14) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-(2-methylpropyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolidin-1-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.8 (s, 1), 9.6 (s, 1),9.6 (br s, 1), 8.4 (s, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (d, 1), 7.0 (s,1), 6.9 (s, 1), 4.4 (d, 1), 4.3 (d, 1), 3.8 (m, 2), 3.4 (m, 4), 3.2 (m,2), 2.8 (s, 3), 1.9 (br s, 4) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(3-(dimethylamino)propyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1),8.3 (d, 1), 8.2 (s, 1), 7.9 (d, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2),4.4 (m, 2), 3.1 (m, 4), 2.8 (s, 9), 2.1 (m, 2) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2,3,4,5,6-pentahydroxyhexyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.1 (s, 1), 10.4 (s, 1),8.3 (d, 1), 8.2 (s, 1), 7.9 (d, 1), 7.6 (d, 2), 7.5 (dd, 1), 7.3 (d, 2),4.3 (s, 2), 4.1 (m, 1), 3.9 (m, 1), 3.7 (d, 1), 3.6 (dd, 1), 3.5 (d, 1),3.4 (dd, 1), 3.3 (m, 2), 3.0 (br, 1), 2.8 (s, 3), 2.5 (s, 1) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-(2-hydroxyethyl)-N'-(1,1-di(hydroxymethyl)-2-hydroxyethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1),8.7 (br, 1), 8.3 (d, 1), 8.1 (s, 1), 7.9 (d, 1), 7.7 (d, 2), 7.6 (dd,1), 7.4 (d, 2), 4.3 (s, 2), 3.8 (s, 1), 3.6 (s, 8), 3.5 (s, 1) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(pyridin-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.6 (d, 1), 8.4 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (m, 2), 7.6 (d, 1),7.5 (m, 1), 7.4 (s, 1), 7.2 (s, 1), 4.5 (s, 2), 4.3 (s, 2), 3.9 (s, 3),2.8 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(1-methylpiperidin4-yl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1),8.4 (d, 2), 8.0 (s, 1), 7.7 (m, 3), 7.4 (d, 2), 3.6 (m, 2), 3.0 (m, 2),2.8 (s, 3), 1.8-2.4 (br, 4) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-(2-hydroxyethyl)l-N'-(2-(morpholin-4-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1),8.3 (d, 1), 8.2 (s, 1), 8.0 (s, 1), 7.7 (m, 2), 7.4 (d, 2), 4.4 (s, 2),3.8 (m, 4), 3.5 (m, 3), 3.2 (m, 5) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((4-ethylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.1 (s, 1), 10.8 (s, 1),8.3 (d, 1), 7.9 (d, 2), 7.7 (m, 3), 7.4 (d, 2), 3.6 (s, 2), 3.4 (br, 3),3.2 (m, 2), 3.0 (m, 3), 2.4 (m, 2), 1.1 (t, 2) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((4-acetylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1),8.4 (d, 1), 8.2 (s, 1), 8.0 (s, 1), 7.7 (m, 3), 7.4 (d, 2), 4.3 (br, 2),2.8-4.0 (br, 8), 2.0 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-(4-methylpiperazin-1-yl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2,3-dihydroxypropyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.1 (s, 1), 10.8 (s, 1),8.3 (d, 1), 8.0 (d, 2), 7.8 (d, 2), 7.7 (d, 1), 7.4 (d, 2), 4.4 (s, 2),3.6 (m, 1), 3.5 (m, 1), 3.2-3.4 (br, 3), 2.5 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR(DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.3 (d, 2), 4.4 (s, 2),3.8 (s, 3), 3.1-3.8 (m, 8), 2.9 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.4 (s, 1), 9.4 (s, 1),8.2 (s, 1), 7.5 (d, 2), 7.3 (d, 2), 7.1 (m, 2), 4.4 (s, 2), 3.1-3.9 (m,8), 2.9 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR(DMSO-d₆ /TFA) 10.8 (s, 1), 9.4 (s, 1),8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.1 (m, 2), 4.4 (s, 2),3.0-3.8 (br m, 8), 2.9 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(((2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR(DMSO-d₆ /TFA) 10.9 (br s, 1), 9.4 (s, 1),8.9 (br s, 2), 8.3 (d, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8 (dd, 1), 7.3 (s,1), 7.2 (s, 1), 4.2 (t, 2), 3.8 (s, 3), 3.6 (t, 2), 3.0 (br s, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((pyridinium-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR(DMSO-d₆ /TFA) 10.9 (br s, 1), 9.4 (s, 1),9.1 (d, 2), 8.6 (t, 1), 8.3 (s, 1), 8.1 (m, 4), 7.8 (dd, 1), 7.3 (s, 1),7.2 (s, 1), 5.8 (s, 2), 3.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((pyridinium-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR(DMSO-d₆ /TFA) 10.8 (s, 1), 9.4 (s, 1),9.1 (d, 2), 8.6 (dd, 1), 8.3 (s, 1), 8.2 (m, 3), 8.1 (d, 1), 7.8 (dd,1), 7.1 (m, 2), 5.9 (s, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1),7.2-8.3 (m, 6), 4.0-4.5 (m, 2), 3.8 (s, 3), 2.3-3.3 (m, 5), 1.1 (m, 3)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (br s,1), 9.4 (s, 1), 9.2 (br s, 1), 7.2-8.3 (m, 6), 4.7 (t, 2), 4.6 (s, 2),3.8 (s, 3), 3.7 (t, 2) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N',N'-dimethyl-N'-(2-hydroxyethyl)ammonio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt, NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1),8.4 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.7 (m, 3), 7.4 (d, 2), 4.6 (s, 2),3.9 (br m, 2), 3.4 (br m, 2), 3.0 (s, 6) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((N',N'-dimethyl-N'-(3-hydroxypropyl)ammonio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt, NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1),8.4 (s, 1), 8.3 (d, 1), 8.0 (s, 1), 7.8 (m, 3), 7.4 (d, 2), 4.5 (s, 2),3.5 (t, 1), 3.4 (m, 3), 3.0 (s, 6), 1.9 (m, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-chloro-5-(N'-methyl-N'-(ethoxycarbonyl)methylamino)benzamide,trifluoroacetic acid salt;

N-(4-methylphenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]benzamide,trifluoroacetic acid salt;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-amino-5-chlorobenzamide,trifluoroacetic acid salt;

N-(4-chlorophenyl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 12.18 (br s, 1), 10.45 (s,1), 9.50 (s, 1), 7.75 (s, 1), 7.69 (s, 1), 7.65 (d, 2), 7.39 (d, 1),7.36 (d, 2) 7.28 (d, 1), 6.98 (d, 1), 6.91 (d, 1), 5.05 (s, 1), 3.85 (s,3) ppm.

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1),8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.4 (d, 1), 7.2 (d, 1),4.4 (s, 2), 3.8 (s, 3), 3.5 (s, 4), 2.9 (s, 6), 2.8 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((4-(((1,1-di(hydroxymethyl)-2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.2 (s, 1), 10.8 (s, 1), 8.7(br, 1), 8.4 (d, 1), 8.2 (s, 1), 7.9 (s, 1), 7.7 (m, 3), 7.4 (d, 2), 5.4(br, 1), 4.3 (s, 2), 3.6 (s, 6) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((3-methyl-2-imino-2,3-dihydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.8 (s, 1), 9.4 (s, 1),8.3 (d, 1), 8.1 (d, 1), 7.9 (br s, 2), 7.8 (dd, 1), 7.6 (s, 1), 7.3 (dd,2), 7.0 (dd, 2), 5.0 (s, 2), 3.9 (s, 3), 3.4 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((1,4,5,6-tetrahydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.9 (s, 1),9.4 (s, 1), 8.4 (d, 1), 8.3 (s, 1), 8.05 (d, 1), 8.0 (s, 1), 7.8 (dd,1), 7.3 (s, 1), 7.2 (s, 1), 4.6 (s, 2), 3.9 (s, 3), 3.2 (bm, 4), 1.8(bm, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(hydroxy)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA-d) 10.9 (s, 1), 9.4 (s, 1),8.4 (d, 1), 8.1 (dd, 1), 7.9 (dd, 1), 7.7 (d, 1), 7.3 (dd, 2), 4.4 (s,2), 3.9 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-aminoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (d, 1),9.2 (br s, 1), 8.4 (d, 1), 8.2 (d, 1), 8.1 (s, 1), 7.8˜8.0 (m, 2), 7.4(d, 1), 7.3 (d, 1), 4.3 (s, 2), 3.9 (s, 3), 3.2˜3.4 (m, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(methoxymethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 10.4 (s, 1),9.4 (d, 1), 8.4 (d, 1), 8.1 (d, 1), 8.0 (s, 1), 7.9 (dd, 1), 7.4 (d, 1),7.3 (d, 1), 4.6 (s, 2), 4.55 (s, 2), 3.9 (s, 3), 3.8 (br s, 4), 3.4 (s,3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (d, 1),9.0 (s, 1), 8.6 (d, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s, 1),7.4 (d, 1), 7.3 (d, 1), 4.6 (s, 2), 3.9 (s, 3), 3.4 (m, 2), 2.6 (m, 2),1.6˜1.8 (m, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(((5-hydroxymethyl-1-methylimidazol-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (d, 1),8.4 (d, 1), 8.1 (d, 1), 7.7 (dd, 1), 7.6 (s, 1), 7.5 (s, 1), 7.3 (d, 1),7.2 (d, 1), 4.5 (s, 2), 4.3 (s, 2), 3.9 (s, 3), 3.6 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-(((imidazol-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (d, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.6 (s, 2), 7.5 (s, 1), 7.3 (d, 1),7.2 (d, 1), 4.4 (s, 2), 3.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamideandN-(5-chloropyridin-2-yl)-2-[((4-((5-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(2:1 mixture), trifluoroacetic acid salt; NMR (DMSO-d₆) 10.77 (s, 0.3),10.75 (s, 0.7), 9.37 (s, 0.3), 9.36 (s, 0.7), 9.04 (d, 0.7), 9.01 (d,0.3), 8.32 (d, 1), 8.06 (d, 1), 7.98 (s, 0.7), 7.88 (dd, 1), 7.80 (s,0.3), 7.45 (t, 0.3), 7.38 (t, 0.7), 7.35 (m, 1), 7.26 (d, 1), 5.36 (s,0.6), 5.34 (s, 1.4), 3.84 (s, 3), 2.23 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-(hydroxymethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamideandN-(5-chloropyridin-2-yl)-2-[((4-((5-(hydroxymethyl)imidazol-1-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(2:1 mixture), trifluoroacetic acid salt; NMR (DMSO-d₆) 10.78 (s, 0.4),10.77 (s, 0.6), 9.37 (s, 1), 9.10 (d, 0.6), 9.01 (d, 0.4), 8.32 (d, 1),8.06 (dd, 1), 8.00 (s, 0.6), 7.88 (dd, 1), 7.81 (s, 0.4), 7.58 (s, 0.4),7.52 (s, 0.6), 7.36 (m, 1), 7.26 (m, 1), 5.40 (s, 0.8), 5.38 (s, 1.2),4.50 (s, 0.8), 4.47 (s, 1.2), 3.84 (1, 3) ppm;

N-(5-chloropyridin-2-yl-2-[((4-((N'-(imino(pyridin-4-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.90 (s, 1), 10.38 (t, 1),9.85 (s, 1), 9.70 (b, 1), 9.53 (s, 1), 9.40 (s, 1), 8.85 (ddd, 2), 8.35(d, 1), 8.08 (d, 1), 7.95 (s, 1), 7.90 (dd, 1), 7.70 (ddd, 2), 7.38 (d,1), 7.25 (d, 1), 4.60 (d, 2), 3.83 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(imino(pyrazin-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.90 (s, 1), 10.60 (b,1), 10.00 (s, 1), 9.70 (s, 1), 9.40 (d, 2), 9.00 (d, 1), 8.90 (d, 1),8.30 (d, 1), 8.10 (d, 1), 7.90 (s, 1), 7.85 (dd, 1), 7.30 (d, 1), 7.25(d, 1), 4.65 (d, 2), 3.80 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-(imidazol-4yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.90 (s, 1), 9.40 (s, 1), 9.00(s, 1), 8.35 (d, 1), 8.10 (d, 1), 8.00 (s, 1), 7.90 (dd, 1), 7.50 (s,1), 7.40 (s, 1), 7.25 (s, 1), 4.20 (s, 2), 3.80 (s, 3), 3.30 (t, 2),3.00 (t, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2,4-dimethylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamideandN-(5-chloropyridin-2-yl)-2-[((4-((2,5-dimethylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(9:1 mixture), trifluoroacetic acid salt; NMR (DMSO-d₆) 10.90 (s, 1),9.42 (s, 0.2), 9.40 (s, 0.8), 8.35 (d, 1), 8.10 (d, 1), 7.90 (m, 2),7.40 (d, 0.2), 7.35 (d, 1), 7.25 (d, 1), 7.20 (d, 0.8), 5.30 (s, 0.4),5.25 (s, 1.6), 3.80 (s, 3), 2.58 (s, 2.5), 2.54 (s, 0.5), 2.18 (d, 2.5),2.13 (d, 0.5) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(N'-amino-N'-methylamino)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.80 (s, 1), 9.30 (s, 1), 8.30(d, 1), 8.20 (s, 1), 8.05 (dd, 1), 7.90 (dd, 1), 7.80 (s, 1), 7.35 (dd,1), 7.25 (d, 1), 4.90 (s, 2), 3.80 (s, 3), 3.65 (t, 2), 3.50 (t, 2),3.15 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 12.20 (s, 1), 11.30 (b,1), 11.10 (s, 1), 8.35 (d, 1), 8.20 (d, 1), 8.10 (s, 1), 7.90 (m, 2),7.70 (b, 2), 7.60 (s, 1), 7.55 (dd, 1), 6.85 (s, 1), 6.80 (s, 1), 5.05(s, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylthio)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 10.1 (s, 1),9.4 (s, 1), 8.3 (s, 1), 8.1 (d, 1), 7.9 (s, 1), 7.8 (d, 1), 7.3 (s, 1),7.2 (s, 1), 4.6 (s, 2), 3.8 (s, 3), 3.8 (s, 4), 2.6 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((imidazolin-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.6 (s, 1), 10.3 (s, 2),9.4 (s, 1), 8.3 (s, 1), 8.1 (d, 1), 7.9 (s, 1), 7.8 (d, 1), 7.4 (s, 1),7.3 (s, 1), 4.5 (s, 2), 3.8 (s, 3), 3.8 (s, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (d, 1),8.4 (d, 1), 8.1 (d, 1), 8.1 (d, 1), 7.8 (d, 1), 7.7 (d, 1), 7.3 (d, 1),7.2 (d, 1), 4.6 (d, 2), 3.9 (s, 3), 3.6 (m, 2), 2.9˜3.2 (m, 5), 2.2 (m,2) ppm; and

N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (d, 1),8.3 (d, 1), 8.1 (d, 2), 7.8 (d, 1), 7.6 (s, 1), 7.35 (s, 1), 7.3 (s, 1),7.0 (s, 1), 6.9 (s, 1), 5.1 (s, 2), 3.9 (s, 3), 3.2 (m, 2), 1.2 (t, 3)ppm.

E. To methylamine (2.0 M in tetrahydrofuran, 16 mL, 32 mmol) was added asolution ofN-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(3.0 g, 6.3 mmol) in DMF (10 mL) and the mixture stirred at ambienttemperature. After 4 hours the reaction mixture was poured into water(100 mL), concentrated in vacuo to remove the tetrahydrofuran andextracted with ethyl acetate (2×75 mL). The combined organics werewashed with brine (75 mL), dried over MgSO₄ and concentrated of allvolatiles in vacuo. Purification by flash chromatography on silica gelafforded 1.1 g (38% yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamideas a yellow solid; NMR (DMSO-d₆ /TFA) 11.4 (s, 1), 11.0 (s, 1), 8.9 (brs, 2), 7.6-8.4 (m, 7), 4.2 (m, 2), 2.6 (m, 3) ppm.

F. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (CDCl₃) 9.8 (br, 1), 9.1 (br, 1), 8.3 (d, 1), 7.9 (d, 1), 7.6 (dd,1), 7.5 (s, 1), 7.1 (d, 1), 7.0 (d, 1), 3.9 (s, 3), 3.7 (s, 2), 2.4 (s,3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.6 (s, 1), 9.0 (s, 1), 8.3 (s, 1), 8.1(d, 1), 8.0 (s, 1), 7.8 (dd, 1), 7.4 (d, 2), 4.1 (s, 2), 3.5 (d, 2), 3.3(d, 2), 3.1 (d, 4), 2.8 (s, 3), 2.6 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide; NMR (DMSO-d₆) 8.3 (s, 1), 8.1 (d, 1), 7.9 (s, 2),7.8 (dd, 1), 7.6 (br, 1), 7.4 (s, 2), 7.3 (br, 1), 3.6 (s, 2), 2.9 (br,8), 2.3 (s, 3), 1.4 (s, 9) ppm;

5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-(((methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole;

N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1), 9.6 (s, 1), 7.2-8.4 (m, 6), 4.4 (s, 2), 3.7(m, 4), 3.3 (m, 4), 2.9 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((ethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((ethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((-1,2,4-oxadiazol-3-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1), 9.6 (s, 1), 9.4 (s, 1), 8.4 (d, 1), 8.1 (d,1), 7.9 (dd, 1), 7.8 (s, 1), 7.4 (d, 1), 7.2 (d, 1), 3.9 (s, 3), 3.8 (s,2), 3.6 (s, 2), 2.2 (s, 3) ppm.

G. A suspension ofN-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.70 g, 1.6 mmol), N-hydroxy-N-methylamine hydrochloride (0.26 g, 3.2mmol), K₂ CO₃ (0.94 g, 3.2 mmol) and triethylamine (0.88 mL, 6.4 mmol)in DMF (30 mL) was stirred at ambient temperature. After 16 hours, themixture was poured onto ice water (200 mL) and the resulting precipitatecollected by filtration. Purification by HPLC on a C18 Dynamax columnwith acetonitrile in water gradient with 0.1% trifluoroacetic acidaffordedN-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-hydroxyamino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 11.2 (s,1), 10.8 (s, 1), 8.4 (d, 1), 8.2 (s, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (d,1), 7.4 (d, 2), 4.6 (d, 1), 4.5 (d, 1), 3.1 (s, 3) ppm.

H. In a similar manner, the following compound was prepared:

N-(5-chloropyridin-2-yl)-2-[((4-(N'-methyl-N"-aminoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (s, 1), 8.1 (d, 1), 7.8 (d, 1), 7.7 (s, 1), 7.4 (s, 2), 7.3 (s, 1),7.2 (s, 1), 4.6 (s, 2), 3.8 (s, 3) ppm.

I. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.20 g, 0.4 mmol) in DMF (5 mL) were added methyl2-chloro-4(trifluoromethyl)pyrimidine-5-carboxylate (0.12 g, 0.48 mmol)and diisopropylethylamine (0.10 g, 0.8 mmol). The mixture was stirred atambient temperature for 16 hours, and then poured onto brine (10 mL) andextracted with ethyl acetate (3×25 mL). The combined organics werewashed with brine (10 mL), dried over Na₂ SO₄ and concentrated in vacuo.Purification by chromatography on silica gel afforded 0.26 g (92% yield)ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-trifluoromethyl-5-(methoxycarbonyl)pyrimidin-2-yl)amino)methyl)-3-chlorothlophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 7.3-8.9 (m, 7), 4.9 (m, 2),3.9 (s, 3), 3.8 (s, 3), 3.2 (s, 3) ppm.

J. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-trifluoromethyl-5-(methoxycarbonyl)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1), 7.3-9 (m, 7), 4.9 (s, 2),3.8 (s, 3), 3.8 (br s, 4), 3.2 (s, 3), 2.9 (br s, 4), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(4-methyloxazolin-2-yl)amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (CDCl₃) 9.0 (s, 1), 8.6 (s, 1), 8.3 (d, 1), 8.2 (d, 1), 7.6 (d, 1),7.4 (s, 1), 7.3 (d, 1), 7.1 (s, 1), 4.4 (m, 3), 4.1 (m, 1), 3.9 (s, 3),3.8 (t, 1), 3.3 (q, 2), 1.2 (d, 3), 1.1 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(cyanomethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1), 9.4 (s, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd,1), 7.8 (s, 1), 7.4 (d, 1), 7.2 (d, 1), 3.9 (s, 3), 3.7 (s, 2), 3.5 (s,2), 2.2 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(4-(ethoxycarbonyl)oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.9 (s, 1), 9.5 (s, 1), 9.4 (s, 1), 8.2(d, 1), 8.1 (d, 2), 7.9 (dd, 1), 7.6 (m, 2), 7.2 (s, 2), 4.6 (s, 2), 3.9(t, 2), 3.8 (s, 3), 34 (t, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-(ethoxycarbonyl)oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1)7 9.5 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 8.0(s, 1), 7.8 (s, 1), 7.7 (dd, 1), 7.55 (m, 1), 7.3 (m, 2), 5.6 (s, 1),5.4 (s, 1), 4.4 (s, 2), 4.1 (q, 2), 3.6 (m, 4), 2.95 (s, 2), 2.9 (m, 4),1.2 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((3-((methylthio)methyl)-1,2,4-oxadiazol-5-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1), 9.4 (s, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd,1), 7.8 (s, 1), 7.4 (d, 1), 7.2 (d, 1), 4.0 (s, 2), 3.9 (s, 3), 3.8 (s,2), 3.6 (s, 2), 2.3 (s, 3), 2.1 (s, 3) ppm; and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1), 9.4 (s, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd,1), 7.8 (s, 1), 7.4 (d, 1), 7.2 (d, 1), 4.5 (s, 2), 4.0 (s, 2), 3.9 (s,3) ppm. 3.6 (s, 2), 3.3 (s, 3), 2.3 (s, 3) ppm.

K. In a manner similar to that described in Paragraph I above,N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.5 g, 3 mmol) reacted with 2-chloro-5-methyl-4,5-dihydrooxazoline (2.7g, 23 mmol) and triethylamine (0.78 mL, 5.6 mmol) to affordN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(5-methyl-4,5-dihydrooxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.Purification by HPLC on a C18 Dynamax column with 20-80% acetonitrile inwater gradient with 0.1% trifluoroacetic acid afforded thetrifluoroacetic acid salt as a white solid: NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.4 (s, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.5 (s, 1), 7.4 (s,1), 7.3 (s, 1), 4.4 (s, 2), 4.2 (m, 1), 3.8 (s, 3), 3.2 (m, 2), 2.8 (s,3), 1.4 (d, 3) ppm.

L. In a similar manner, the following compound was made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (d, 1), 8.2 (br s, 1), 8.1 (d, 1), 8.0 (br s, 1), 7.7 (dd, 1), 7.4(d, 1), 7.3 (d, 1), 4.6 (s, 2), 3.9 (s, 3), 3.1˜3.3 (m, 6) ppm.

M. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.50 g, 1.0 mmol) in DMF (5 mL) were added 2-fluoropyridine (1 mL, 12mmol) and cesium carbonate (0.33 g, 1.0 mmol) and the mixture was heatedat 125° C. After 72 hours the mixture was cooled to ambient temperature,filtered and acidified with aqueous trifluoroacetic acid. Purificationby HPLC on a C18 Vydac column with acetonitrile in water gradient with0.1% trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(pyridin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt as a white solid: NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.4 (s, 1), 8.4 (d, 1), 8.1 (d, 1), 8.0-7.9 (m, 3), 7.8 (dd, 1), 7.7(s, 1), 7.4 (s, 1), 7.2 (d, 1), 7.1 (d, 1), 6.9 (t, 1), 4.8 (s, 2), 3.8(s, 3), 3.2 (s, 3) ppm.

N. To a suspension ofN-(4-chlorophenyl)-2-[((4,5-di(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.075 g, 0.14 mmol) in acetonitrile (3 mL) in a pressure vessel wasadded propylamine (0.025 mL, 0.30 mmol). The vessel was sealed and thesuspension heated at 50° C. for 10 days, with additional 0.025 mLportions of propylamine being added after 3 and 9 days. The mixture wascooled to ambient temperature and concentrated of all volatiles invacuo. The resulting solid was dissolved in acetonitrile, water andtrifluoroacetic acid and purified by HPLC on a C18 Vydac column with25-60% acetonitrile in water gradient with 0.1% trifluoroacetic acid toaffordN-(4-chlorophenyl)-2-[((3-chloro-4,5-di((n-propyl)aminomethyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 11.3 (s,1), 10.8 (s, 1), 8.9 (br s, 2), 8.7 (br s, 2), 8.4 (d, 1), 7.4-8.0 (m,6), 4.6 (s, 2), 4.3 (s, 2), 3.0 (m, 4), 1.6 (m, 4), 0.9 (m, 6) ppm.

O. In a manner similar to that described in Paragraph I above,N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.86 g, 1.7 mmol) reacted with 2-methanesulfonyl-4-aminopyrimidine(0.60 g, 3.5 mmol) and diisopropylethylamine (0.90 mL, 5.2 mmol) in DMSOat 90° C. Purification by chromatography on silica gel afforded 0.78 g(76% yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-aminopyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a light brown solid; NMR (DMSO-d₆) 10.9 (s, 1), 9.4 (s, 1), 8.4 (d,1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (d, 1), 7.5 (s, 1), 7.4 (d, 1), 7.3 (d,1), 6.0 (br s, 1), 5.9 (d, 1), 4.8 (s, 2), 3.9 (s, 3), 3.0 (s, 3) ppm.

P. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(4-aminopyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.90 (s, 1H), 9.38 (s, 1H), 8.36 (d, 1H), 8.10 (d, 1H),7.90 (dd, 1H), 7.69 (s, 1H), 7.62 (d, 1H), 7.38 (d, 1H), 7.28 (d, 1H),5.96-5.92 (m, 2H), 5.80-5.74 (m, 2H), 4.35 (s, 2H), 3.90 (s, 3H) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(4-(methylamino)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 11.90 (br s, 1H), 10.90 (s, 1H), 9.40 (s, 1H), 8.50 (s,1H), 8.30 (d, 1H), 8.10 (d, 1H), 8.00-7.50 (m, 3H), 7.40 (d, 1H), 7.25(d,₁ H), 6.20-6.00 (m, 2H), 4.604.35 (m, 2H), 4.00-3.80 (m, 3H),2.90-2.80 (m, 3H) ppm.

Q. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(2.1 g, 4.1 mmol) in DMF (20 mL) was added a 2,2,2-trifluoroethylamine(3.2 mL, 41 mmol). The mixture was heated at 75° C. for 18 hours, thencooled to ambient temperature and concentrated in vacuo to remove excess2,2,2-trifluoroethylamine. Water was added and the mixture was extractedwith methylene chloride. The organic layer was dried over Na₂ SO₄ andconcentrated in vacuo. Purification by flash chromatography on silicagel afforded 2.2 g (95% yield) ofN-(5-chloropyridin-2-yl)-2-[((4-(((2,2,2-trifluoroethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.8 (s, 1) 9.4 (s, 1), 8.2 (d, 1), 8.1 (d, 1), 8.0(s, 1), 7.8 (dd, 1), 7.2 (d, 2), 4.2 (s, 2), 4.1 (q, 2), 3.8 (s, 3) ppm.

R. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.57 g, 1.1 mmol) in THF (23 mL) was added methyl chlorothiolformate(0.10 mL, 1.15 mmol) at 0° C. and the mixture stirred for 2 hours. Thereaction was concentrated in vacuo and the residue dissolved in ethylacetate and 1 M HCl. The layers were separated and the organic layer waswashed with brine, dried over sodium sulfate and concentrated in vacuo.Purification by flash chromatography on silica gel afforded 0.26 g (42%yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((methylthio)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white solid; NMR (DMSO-d₆) 10.9 (s, 1), 9.4 (s, 1), 8.4 (d, 1), 8.1(d, 1), 7.9 (d, 1), 7.6 (s, 1), 7.4 (s, 1), 7.2 (s, 1), 4.4 (s, 2), 3.9(s, 3), 3.0 (s, 3), 2.2 (s, 3) ppm.

S. In a similar manner, the following compound was made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-((phenylthio)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (CDCl₃) 9.0 (s, 1), 8.8 (s, 1), 8.2 (d, 1), 8.1 (d, 1), 7.6 (d, 1),7.5 (m, 3), 7.4 (m, 3), 7.0 (s, 1), 4.6 (s, 2), 3.9 (s, 3), 3.5 (q, 2),1.2 (m, 3) ppm.

T. In a manner similar to that described in Paragraph C above, DMF (6mL) was added to a mixture ofN-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.87 g, 1.73 mmol) and imidazole (0.35 g, 5.18 mmol) at ambienttemperature. The mixture was heated at 45° C. for 15 hours. Aftercooling, additional imidazole (0.25 g, 3.67 mmol) was added, and theheating was continued for 5 days. The mixture was cooled in an ice bath,and trifluoroacetic acid (0.5 mL) was added dropwise. Purification byHPLC on a C18 Dynamax column with 20-70% acetonitrile in water gradientwith 0.1% trifluoroacetic acid gave 0.85 g ofN-(5-chloropyridin-2-yl)-2-[((4-((imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a white solid; NMR (DMSO-d₆ /TFA) 10.85(s, 1), 9.40 (s, 1), 9.20 (s, 1), 8.25 (d 1), 8.05 (d, 1), 7.95 (s, 1),7.80 (dd, 1), 7.70 (s, 1), 7.60 (s, 1), 7.30 (d, 1), 7.20 (d, 1), 5.40(s, 2), 3.80 (s, 3) ppm.

U. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.85 (s, 1), 9.40 (s, 1),8.25 (d, 1), 8.05 (d, 1), 7.80 (m, 2), 7.50 (s, 2), 7.30 (d, 1), 7.20(d, 1), 5.30 (s, 2), 3.80 (s, 3), 2.60 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1,2,4-triazol-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 10.3 (s., 1),9.4 (s, 1), 9.2 (s, 1), 8.4 (d, 1), 8.1 (m, 2), 7.9 (m, 1), 7.3 (d, 1),7.2 (d, 1), 5.6 (s, 2), 3.9 (s, 3), ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2,6-diaminopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, andN-(5-chloropyridin-2-yl)-2-[((4-((2,6-diaminopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.90 (s, 0.5), 10.85 (s, 0.5),9.40 (s, 0.5), 9.38 (s, 0.5), 8.50 (b, 0.6), 8.34 (m, 1), 8.18 (b, 0.4),8.14 (s, 1), 8.04-8.09 (m, 2), 7.94 (b, 1), 7.88 (dd, 1), 7.72 (b, 0.4),7.56 (s, 0.6), 7.36 (m, 2), 7.26 (dd, 1), 5.28 (s, 1), 5.20 (s, 1), 3.85(s, 1.5), 3.84 (s, 1.5) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-1,2-dihydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.85 (s, 1), 9.40 (s, 1),8.85 (d, 1), 8.50 (d, 1), 8.30 (d, 1), 8.10 (d, 1), 7.80 (dd, 1), 7.75(s, 1), 7.30 (s, 1), 7.25 (s, 1), 7.05 (dd, 1), 5.25 (s, 2), 3.80 (s, 3)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-1(2H)-pyridin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.90 (s, 1), 9.40 (s, 1),8.60 (b, 2), 8.30 (d, 1), 8.10 (d, 1), 8.00 (d, 1), 7.80-7.90 (m, 2),7.45 (s, 1), 7.30 (s, 1), 7.25 (s, 1), 7.10 (d, 1), 6.90 (m, 1), 5.30(s, 2), 3.80 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((3,5-diamino-4H-1,2,4-triazol-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (s, 1), 8.1 (d, 1), 8.1 (s, 1), 7.9 (d, 1), 7.8 (s, 1), 7.3 (s, 1),7.2 (s, 1), 5 (s, 2), 3.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrothiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA-d) 8.3 (s, 1), 8.1 (d, 1),7.8 (s, 1), 7.8 (dd, 1), 7.3 (dd, 2), 4.7 (s, 2) 3.9 (t, 2), 3.8 (s, 3)3.5 (t, 2) ppm; and

N-(5-chloropyridin-2-yl)-2-[((4-((4-imino-1(4H)-pyridinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.85 (s, 1), 9.40 (s, 1), 8.30(d, 1), 8.15 (m, 4), 8.05 (d, 1), 7.90 (s, 1), 7.85 (dd, 1), 7.35 (d,1), 7.25 (d, 1), 6.80 (d, 2), 5.30 (s, 2), 3.80 (s, 3) ppm.

V. In a similar manner to that described above in Paragraph T,N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.31 g, 0.6 mmol) and pyrazole (0.56 g, 6.7 mmol) were mixed in DMF (20mL). The mixture was heated at 50° C. for 2 days. It was then added towater and the precipitate was isolated by filtration. The solid wasdissolved in CH₂ Cl₂ (200 mL) and washed with water (2×50 mL) and brine(2×50 mL), dried (Na₂ SO₄) and concentrated. Purification by silica gelchromatography using 20:1 CH₂ Cl₂ :CH₃ OH as the eluent andprecipitation affordedN-(5-chloropyridin-2-yl)-2-[((4-((N'-(pyrazol-3-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white solid; NMR (DMSO-d₆) 11.55 (br s, 1H), 10.90 (s, 1H), 9.35(s, 1H), 8.36 (d, 1H), 8.10 (d, 1H), 7.90 (dd, 1H), 7.64 (s, 1H),7.40-7.25 (m, 3H), 5.60 (br s, 1H), 5.50 (s, 1H), 4.20 (s, 2H), 3.85 (s,3H) ppm.

W. In a manner similar to that described in Paragraph I above, to asolution of 2-methoxy-3,4,5,6-tetrahydropyridine (0.27 g, 2.4 mmol),N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.0 mmol) and DMF (10 mL) at ambient temperature was addedN,N-diisopropylethylamine (0.65 g, 5.0 mmol). The solution was thenwarmed to 70° C. for 3 days. It was then poured into water. The mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, dried (Na₂ SO₄) and concentrated. Purification by HPLC on a C18Dynamax column with acetonitrile in water gradient with 0.1%trifluoroacetic acid afforded the trifluoroacetic acid salt ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3,4,5,6-tetrahydropyridin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (d, 1), 8.4 (d,1), 9.2 (br s, 1), 8.3 (d, 1), 8.2 (d, 1), 7.9 (m, 2), 7.4 (d, 1), 7.3(d, 1), 4.6 (d, 2), 3.9 (s, 3), 2.6˜3.4 (7), 1.6 (m, 3) ppm.

X. In a manner similar to that described in Paragraph O above, a mixtureof 2-amino-4-chloro-6-methylpyrimidine (0.3 g, 2.1 mmol),N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.25 g, 0.5 mmol), N,N-diisopropylethylamine (0.44 mL, 2.5 mmol), andDMSO (5 mL) was heated under N₂ at 100° C. for 15 hours. The mixture wascooled in ice bath, and trifluoroacetic acid (0.5 mL) was addeddropwise. Purification by HPLC on a C18 Dynamax column with 20-70%acetonitrile in water gradient with 0.1% trifluoroacetic acid gave 0.24g ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-amino-6-methylpyrimidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a white solid; NMR (DMSO-d₆ /TFA) 10.85(s, 1), 9.40 (s, 1), 8.30 (1, 1), 8.10 (d, 1), 7.80 (d, 1), 7.60 (m, 2),7.30 (s, 1), 7.25 (s, 1), 6.35 (s, 0.3), 6.30 (s, 0.7), 4.80 (s, 1.5),4.60 (s, 0.5), 3.80 (s, 3), 2.22 (s, 2.2), 2.18 (s, 0.8) ppm.

Y. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-chloropyrimidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.85 (s, 1), 9.40 (s, 1), 8.30(d, 1), 8.10 (d, 1), 8.09 (b, 1), 7.90 (dd, 1), 7.60 (s, 1), 7.35 (s,1), 7.25 (s, 1), 6.70 (d, 1), 4.65 (b, 2), 3.80 (s, 3), 3.30 (s, 3) ppm;and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(pyridin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.85 (s, 1), 9.40 (s, 1),8.30 (d, 1), 8.20 (b, 2), 8.10 (d, 1), 7.80 (dd, 1), 7.60 (s, 1), 7.30(s, 1), 7.25 (s, 1), 7.00 (d, 2), 4.75 (s, 2), 3.80 (s, 3), 3.20 (s, 3)ppm.

Z. In a manner similar to Paragraph E above,N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.0 mmol) in DMF (5 mL) was reacted with dimethylamine (1.33 Min tetrahydrofuran, 7.5 mL, 10 mmol) to giveN-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;which was purified by lyophilization from aqueous HCl to affordN-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;hydrochloric acid salt, as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 10.1 (br s, 1), 9.5 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8(dd, 1), 7.3 (dd, 2), 4.3 (br s, 2), 3.9 (s, 3), 2.8 (br s, 6) ppm.

AA. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 2 Compounds of Formula (Ic)

A. To a suspension ofN-(4-chlorophenyl)-2-[((5-(bromomethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.75 g, 1.5 mmol) in methylene chloride (25 mL) was added1-methylpiperazine (0.8 mL, 7.3 mmol). The resultant mixture was stirredat ambient temperature for 18 hours, then diluted with methylenechloride. The mixture was washed with saturated aqueous NaHCO₃ and theaqueous layer was back-extracted with methylene chloride. The combinedorganics were dried over MgSO₄ and concentrated in vacuo. The resultingsolid was dissolved in acetonitrile, water and trifluoroacetic acid.Purification by HPLC on a C18 Dynamax column with 20-80% acetonitrile inwater gradient with 0.1% trifluoroacetic acid affordedN-(4-chlorophenyl)-2-[((5-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.7 (s, 1),8.3 (d, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.3 (s, 2), 7.2 (dd, 1), 4.5 (s,2), 3.6-3.2 (br m, 8), 2.8 (s, 3) ppm.

B. In a similar manner to that described in Paragraph A above,N-(4-chlorophenyl)-2-[((5-(bromomethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.5 g, 1.0 mmol) was reacted with thiomorpholine (0.5 mL, 4.8 mmol).Purification by flash chromatography on silica gel afforded 0.4 g (73%yield) ofN-(4-chlorophenyl)-2-[((5-((thiomorpholin-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;as a pale yellow powder; NMR (CDCl₃) 11.0 (s, 1), 9.0 (s, 1), 8.2 (d,1), 7.8 (d, 2), 7.5 (d, 1), 7.4 (d, 2), 7.4 (s, 1), 7.2 (dd, 1), 3.7 (s,2), 2.8 (m, 4), 2.7 (m, 4) ppm.

C. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-[((3-chloro-5-(((2-(dimethylamino)ethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.7 (d,2), 7.6 (dd, 1), 7.4 (d, 2), 7.2 (s, 1), 4.0 (s, 2), 3.3 (m, 2), 2.8-2.7(m, 8) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-5-((N'-methyl-N'-(2-dimethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.8 (s, 1), 8.4 (d, 1), 7.9 (s, 1), 7.7(d, 2), 7.6 (dd, 1), 7.4 (s, 1), 7.3 (d, 2), 4.6 (s, 2), 3.5 (s, 4), 2.8(s, 6), 2.7 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-5-((4-(ethoxycarbonylmethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.2 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.3-8.0 (m, 7), 4.4(s, 2), 4.2 (m, 4), 3.3 (br d, 8), 1.2 (t, 3) ppm;

N-(4-chlorophenyl)-2-[((3-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(morpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(N'-methyl-N'-(2-hydroxyethyl)amino)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(N'-methyl-N'-(ethoxycarbonylmethyl)amino)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(N',N'-di(2-hydroxyethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-((4-(((2-(2-methoxyethoxy)ethoxy)methyl)carbonyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(((N'-(3-dimethylaminophenyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(pyrrolidin-1-yl)methylbenzamide;

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(dimethylamino)methylbenzamide;

N-(4-chlorophenyl)-2-[((3-(4-methylpiperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(amino)methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-6-(4-methylpiperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-6-(4-(ethoxycarbonylmethyl)piperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.4 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.4-8.0 (m, 9), 4.1(m, 2), 3.6 (s, 2), 3.2 (s, 2), 3.1 (m, 1), 2.7 (m, 1), 2.4 (br m, 6),1.2 (t, 3) ppm.

D. To a suspension ofN-(4-chlorophenyl)-2-[((3-(bromomethyl)benzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide(0.075 g, 0.14 mmol) in methylene chloride (1.5 mL) in a pressure vesselwas added dimethylamine hydrochloride (0.035 g, 0.43 mmol), followed byBio-Rad AGI-X8 anion exchange resin (0.55 g, 0.7 mmol equivalents, OH⁻form). The vessel was sealed and the mixture was stirred at ambienttemperature for 3.5 hours. The vessel was opened and the reactionmixture diluted with methylene chloride (25 mL) and acetonitrile (25mL), filtered and concentrated in vacuo. Purification by flashchromatography on silica gel, followed by crystallization fromacetonitrile afforded 0.030 g (43% yield) ofN-(4-chlorophenyl)-2-[((3-(dimethylamino)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide,as a crystalline solid; NMR (DMSO-d₆ /TFA) 13.2 (s, 1), 10.7 (s, 1),7.3-8.1 (m, 11), 3.9 (s, 2), 2.1 (s, 6) ppm.

E. In a similar manner, the following compounds were made:

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(pyrrolidin-1-yl)methylbenzamide;

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(dimethylamino)methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-6-(dimethylamino)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((5-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamid.

F. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 3 Compounds of Formula (Id)

A. To a solution ofN-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.52 g, 1.1 mmol) in DMF (12 mL) was added sodium thiomethoxide (0.39g, 5.5 mmol) and the reaction mixture stirred at ambient temperature.After 16 hours, the mixture was poured into water (100 mL) and extractedwith ethyl acetate (2×80 mL). The combined organics were washed withwater (2×80 mL), 1 M hydrochloric acid (2×80 mL) and brine (80 mL),dried over MgSO₄ and concentrated of all volatiles in vacuo.Purification of the resulting solid by flash chromatography on silicagel afforded 0.36 g (68% yield) ofN-(4-chlorophenyl)-2-[((3-chloro-4-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;as a pale yellow solid; NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d,1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 3.7 (s,2), 2.0 (s, 3) ppm.

B. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-[((3-chloro-5-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (CDCl₃) 11.0 (s, 1), 9.2 (s, 1), 8.1 (d, 1), 7.8 (d, 2), 7.5 (d, 1),7.4 (d, 2), 7.1 (dd, 1), 6.9 (s, 1), 3.8 (s, 2), 2.1 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-5-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.7 (s, 1), 9.2 (s, 1), 8.3 (d, 1), 7.9 (d,1), 7.8 (s, 1), 7.3-7.2 (m, 4), 7.4 (s, 1), 7.3 (s, 2), 5.6 (s, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-cyanomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.3 (s, 1), 8.1 (d, 1), 7.8(m, 2), 7.3 (s, 1), 7.2 (s, 1), 3.9 (s, 2), 3.8 (s, 3) ppm.

C. In a manner similar to that described in Paragraph A above,N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.30 g, 0.64 mmol) reacted with sodium imidazole (0.17 g, 1.9 mmol) inDMF (10 mL) to affordN-(4-chlorophenyl)-2-[((3-chloro-4-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.Purification by HPLC on a C18 Dynamax column with acetonitrile in watergradient with 0.1% trifluoroacetic acid afforded two products: Theearlier eluting material affordedN-(4-chlorophenyl)-2-[((3-chloro-4-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt as a cream-colored solid; NMR DMSO-d₆ /TFA)11.1 (s, 1), 10.8 (s, 1), 9.2 (s, 1), 8.3 (d, 1), 8.1 (s, 1), 7.9 (d,1), 7.7 (m, 5), 7.4 d, 2), 5.4 (s, 2) ppm. The later eluting materialaffordedN-(4-chlorophenyl)-2-[((3-chloro-4-(hydroxymethyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;as a white solid; NMR (DMSO-d₆ /TFA) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d,1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 5.4(br, 1), 4.4 (s, 2) ppm.

D. To a solution of 1,2,4-triazole (0.40 g, 5.7 mmol) in DMF (10 mL) wasadded NaH (60% dispersion in mineral oil, 0.23 g, 5.7 mmol) and themixture stirred at ambient temperature. After 10 min,N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.90 g, 1.9 mmol) in DMF (5 mL) was added and stirring continued. After18 hours, the mixture was poured onto water and extracted with methylenechloride. The organic layer was dried over MgSO₄ and concentrated invacuo. Purification by flash chromatography on silica gel afforded 0.99g (77% yield) ofN-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,4-triazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;as a white solid; NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.7 (s, 1), 9.3 (s,1), 8.5 (s, 1), 8.3 (d, 1), 8.0 (s, 1), 7.9 (d, 1), 7.7 (d, 2), 7.6 (dd,1), 7.4 (d, 2), 5.5 (s, 2) ppm.

E. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-[((3-chloro-4-((tetrazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.7 (s, 1), 9.4 (s, 1), 8.3 (d, 1), 8.0(s, 1), 7.85 (d, 1), 7.7 (d, 2), 7.5 (dd, 1), 7.3 (d, 2), 5.7 (s, 2)ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((tetrazol-2-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.7 (s, 1), 9.4 (s, 1), 8.3 (d, 1), 8.1(s, 1), 7.9 (d, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 5.9 (s, 2) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((pyrazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.1 (s, 1), 10.7 (s, 1), 7.3-8.4 (m, 10), 6.3 (s,1), 5.3 (s, 2) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,3-triazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.1 (s, 1), 10.7 (s, 1), 7.3-8.4 (m, 9), 5.3 (s, 2)ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,3-triazol-2-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.9 (s, 1), 7.3-8.5 (m, 10), 5.6 (br s,2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-imino-3-methyl-5-oxoimidazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (br s., 1), 9.4 (s, 1), 8.4 (d, 1),8.1 (d, 1), 7.9 (m, 2), 7.4 (s, 1), 7.3 (m, 2), 4.5 (d, 2), 4.2 (s, 2),3.9 (s, 3), 3.1 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4,5-dichloroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.85 (s, 1), 9.40 (s, 1), 8.30 (d, 1), 8.10 (d, 1),7.80-7.86 (m, 2), 7.65 (s, 1), 7.30 (d, 1), 7.25 (d, 1), 5.20 (s, 2),3.80 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-methyl-4-nitroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.85 (s, 1), 9.40 (s, 1), 8.30 (d, 1), 8.20 (s, 1),8.10 (d, 1), 7.80 (dd, 1), 7.70 (s, 1), 7.30 (d, 1), 7.25 (d, 1), 5.20(s, 2), 3.80 (s, 3), 2.30 (s, 3) ppm.

F. To a solution ofN-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.70 g, 1.5 mmol) in DMF (5 mL) was added 2-(dimethylamino)ethanethiol(2.1 g, 15 mmol), followed by potassium carbonate (1.0 g, 7.2 mmol) andthe reaction stirred at ambient temperature. After 24 hours, the mixturewas poured into water (100 mL) and the resulting solid collected byfiltration, washed with water and dried in vacuo. Purification by flashchromatography on silica gel afforded 0.28 g (35% yield) ofN-(4-chlorophenyl)-2-[((3-chloro-4-(((2-(dimethylamino)ethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;as a cream-colored solid; NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3(d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 3.7(s, 2), 2.5 (t, 2), 2.4 (t, 2), 2.1 (s, 6) ppm.

G. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-[((3-chloro-4-(((methoxycarbonylmethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s,1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 3.8 (s, 2), 3.6 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4,5-dihydropyrazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8, 4 (s, 1), 8.1 (d, 1), 7.9(m, 2), 7.4 (s, 1), 7.2 (d, 2), 4.2 (s, 2), 3.9 (s, 3), 3.1 (t, 2), 2.7(t, 2) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-5-(((methoxycarbonylmethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.0 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.8 (d,2), 7.6 (dd, 1), 7.4 (d, 2), 7.1 (s, 1), 4.1 (s, 2), 3.6 (s, 3), 3.4 (s,2) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-6-((methoxycarbonyl)methylthio)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-5-chloropyridin-2-yl)-2-[((4-((pyrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1H), 9.40 (s, 1H), 8.36 (d, 1H), 8.10 (d, 1H),7.90 (dd, 1H), 7.78 (d, 1H), 7.66 (s, 1H), 7.46 (d, 1H), 7.38 (d, 1H),7.26 (d, 1H), 6.30 (s, 1H), 5.35 (s, 2H), 3.83 (s, 3H) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((hydantoin-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.82 (s, 1H), 9.40 (s, 1H), 8.36 (d, 1H), 8.18 (s, 1H),8.10 (d, 1H), 7.90 (dd, 1H), 7.70 (s, 1H), 7.38 (d, 1H), 7.27 (d, 1H),4.46 (s, 2H), 3.97 (s, 2H), 3.88 (s, 3H) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylimino)pyrrolidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (d, 1), 9.3 (m, 1), 8.4 (d, 1), 8.1(d, 1), 8.0 (s, 1), 7.9 (m, 2), 7.4 (d, 1), 7.3 (d, 1), 4.6 (s, 2), 3.9(s, 3), 3.6 (t, 2), 3.4 (m, 2), 3.0 (t, 3), 2.1 (m, 2), 1.2 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-iminopiperidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.3 (d, 1), 9.1 (s, 1), 8.6 (br s, 1),8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.6 (d, 1), 7.4 (d, 1), 7.3 (d, 1),4.6 (s, 2), 3.9 (s, 3), 3.4 (m, 2), 2.7 (m, 2), 1.9 (m, 4) ppm.

H. To 2-methoxyethanol (20 mL) at 0° C. was added NaH (0.45 g, 11 mmol).The solution was warmed to ambient temperature and stirred for 16 hours.N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.3 mmol) was added and stirring continued for 3 hours. Themixture was then heated at 65° C. for 4 hours, then poured onto icewater (200 mL). The resulting solid was collected by filtration, washedwith water and 50% ether/hexanes, and dried in vacuo to afford 0.65 g(52% yield) ofN-(4-chlorophenyl)-2-[((3-chloro-4-((2-(2-methoxyethoxy)ethoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;as a pale yellow solid: NMR (DMSO-d₆ /TFA) 11.1 (s, 1), 10.7 (s, 1), 8.3(d, 1), 7.9 (d, 2), 7.7 (d, 2), 7.6 (d, 1), 7.4 (s, 1), 7.4 (s, 1), 4.4(s, 2), 3.5 (m, 6), 3.4 (m, 2), 3.2 (s, 3) ppm.

I. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-[((3-chloro-4-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.2 (s, 1), 10.8 (s, 1), 8.4 (d, 1), 7.9 (s, 1), 7.8 (s,1), 7.7 (d, 2), 7.6 (d, 1), 7.4 (d, 2), 4.4 (d, 2), 3.6 (m, 4), 3.5 (m,6), 3.4 (m, 2), 3.2 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((2-methoxyethoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-(((2,2-dimethyldioxolan-4-yl)methoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 8.0 (d, 2), 7.7 (d,2), 7.6 (d, 1), 7.4 (d, 2), 4.5 (s, 2), 4.2 (t, 1)4.0 (t, 1), 3.6 (m,1), 3.4 (d, 2), 1.2 (d, 6) ppm.

J. In a manner similar to that described in Paragraph F above, to asolution of 3-dimethylamino-5-methylpyrazole (0.38 g, 3.0 mmol),N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.0 mmol), and DMSO (10 mL) was added K₂ CO₃ (1.0 g, 7.2 mmol).The mixture was stirred at ambient temperature for 16 hours, then it waspoured into H₂ O. The solid was isolated by filtration. Purification byHPLC on a C18 Dynamax column with 25-95% acetonitrile in water gradientwith 0.1% trifluoroacetic acid afforded the trifluoroacetic acid saltsofN-(5-chloropyridin-2-yl)-2-[((4-((3-dimethylamino-5-methylpyrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.90 (s, 1H), 9.50 (s, 1H), 8.40 (d, 1H), 8.10 (d, 1H),7.90 (dd, 1H), 7.60 (s, 1H), 7.40 (d, 1H), 7.25 (d, 1H), 6.45 (s, 1H),4.90 (s, 2H), 3.90 (s, 3H), 2.50 (s, 6H), 2.25 (s, 3H) ppm, andN-(5-chloropyridin-2-yl)-2-[((4-((3-dimethylamino-5-methylpyrazol-2-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.90 (s, 1H), 9.40 (s, 1H), 8.40 (d, 1H), 8.10 (d, 1H),7.90 (dd, 1H), 7.38 (s, 1H), 7.28 (d, 1H), 7.25 (d, 1H), 5.60 (s, 1H),5.00 (s, 2H), 3.90 (s, 3H), 2.70 (s, 3H), 2.20 (s, 3H) ppm.

K. In a similar manner, the following compound was made:

N-(5-chloropyridin-2-yl)-2-[((4-((5-aminotetrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s., 1),8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 2), 7.7 (s, 1), 7.3 (d, 1), 7.2 (d, 1),5.3 (s, 1), 3.9 (s, 3) ppm.

L. In a manner similar to that described in Paragraph J above, to asolution of N,N-diethylhydroxylamine (0.45 g, 5.0 mmol),N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.51 g, 1.0 mmol), and DMSO (10 mL) was added K₂ CO₃ (0.68 g, 4.9mmol). The mixture was stirred at 40° C. for 2 stirred at ambienttemperature. After 0.5 hours, water (2 mL) was added resulting in aheterogeneous mixture. LiOH.H₂ O (large excess) was added and themixture stirred for 2 hours, then concentrated in vacuo. Purification byHPLC on a C18 Dynamax column with acetonitrile in water gradient with0.1% trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-carboxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a white solid: NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.4 (s, 1), 8.3 (s, 1), 8.1 (d, 1), 7.9 (d, 1), 7.5 (s, 1), 7.4 (s,1), 7.3 (s, 1), 4.3 (s, 2), 3.9 (s, 3), 3.3 (t, 2), 2.8 (s, 3), 2.4 (t,2) ppm.

J. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 6 Compounds of Formula (Ij)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.6 g, 3.2 mmol) and diisopropylethylamine (1.7 mL, 9.6 mmol) in CH₂Cl₂ (10 mL) at 0° C. was added 2-chloroacetyl chloride (0.25 mL, 3.2mmol). The mixture was stirred and allowed to warm to ambienttemperature. After 7 hours, 4-hydroxypiperidine (0.65 g, 6.4 mmol) wasadded and the reaction stirred for 16 hours. The mixture wasconcentrated of all volatiles in vacuo and the resulting oil purified byHPLC on a C18 Dynamax column with acetonitrile in water gradient with0.1% trifluoroacetic acid to affordN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(((4-hydroxypiperidin-1-yl)methyl)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.5 (br s, 1), 9.4 (s, 1), 8.4 (s, 1), 8.1 (d, 1), 7.9 (d, 1), 7.7(s, 1), 7.4 (s, 1), 7.3 (s, 1), 4.5 (m, 2), 4.3 (m, 2), 3.9 (m, 1), 3.9(s, 3), 3.6 (m, 1), 3.4 (m, 1), 3.2 (m, 2), 3.0 (s, 3), 2.0 (m, 2), 1.7(m, 2) ppm.

B. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((2-chloroethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.1 g, 1.8 mmol) in DMF (5 mL) was added Cs₂ CO₃ (5.7 g, 18 mmol),followed by 4-hydroxypiperidine (0.27 g, 2.6 mmol). The mixture wasstirred at ambient temperature for 16 hours, then filtered andconcentrated in vacuo. Purification of the resulting oil by flashchromatography on silica gel afforded 1.0 g (82% yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((2-(4-hydroxypiperidin-1-yl)ethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (br s, 1), 9.4 (s,1), 8.4 (s, 1), 8.1 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.4 (s, 1), 7.3 (s,1), 4.3 (s, 2), 3.9 (m, 1), 3.9 (s, 3), 3.7 (m, 2), 3.5 (m, 2), 3.3 (m,2), 3.2 (m, 1), 3.0 (m, 1), 2.8 (m, 3), 2.0 (m, 1), 1.8 (m, 2), 1.6(m, 1) ppm.

C. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.3 (s, 1), 8.1 (d, 1), 7.9(d, 1), 7.8 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 4.4 (s, 2), 3.9 (s, 3), 3.6(m, 6), 3.1 (br m, 2), 2.8 (s, 3), 2.1 (m, 2), 1.9 (m, 2) ppm.

D. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 7 Compounds of Formula (Ik)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.10 g, 0.20 mmol) in DMF (3 mL) were added triethylamine (0.28 mL, 2.0mmol) and 1H -pyrazole-1-carboxamidine hydrochloride (0.30 g, 2.0 mmol).The mixture was stirred at ambient temperature for 15 hours, then heatedat 45° C. for 3 hours. The cooled mixture was acidified withtrifluoroacetic acid and purified by HPLC on a C18 Dynamax column with20-70% acetonitrile in water gradient with 0.1% trifluoroacetic acid toaffordN-(5-chloropyridin-2-yl)-2-[((4-(((amidino)(methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt as white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.4 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.6 (s, 1), 7.4 (brs, 4), 7.3 (s, 1), 7.2 (s, 1), 4.5 (s, 2), 3.8 (s, 3), 2.9 (s, 3) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 8 Compounds of Formula (Im)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.70 g, 1.4 mmol) in MeOH (30 mL) was added triethylamine (3 mL, 22mmol) and ethyl acetimidate hydrochloride (large excess). The reactionwas stirred at ambient temperature for 16 hours, then concentrated ofall volatiles in vacuo. Purification of the residual oil by HPLC on aC18 Dynamax column with acetonitrile in water gradient with 0.1%trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-iminoethyl)-N'-methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA)(rotational isomers observed) 10.9 (s, 1), 9.4 (s, 1), 9.3 (br s, 1),8.6 (br s, 1), 8.4 (s, 1), 8.1 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.4 (s,1), 7.3 (s, 1), 4.6 (s, 2), 3.9 (s, 3), 3.1 (s, 3), 2.3 (s, 3) ppm.

B. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(3.0 g, 6.0 mmol) in DMF (30 mL) were added N,N-diisopropylethylamine(1.94 g, 15 mmol) and 2-methylthioimidazoline hydroiodide (1.9 g, 7.8mmol). The mixture was heated at 90° C. for 20 hours. The cooled mixturewas poured into water, extracted with ethyl acetate, dried (MgSO₄) andconcentrated in vacuo. Purification by HPLC on a C18 Dynamax column with20-70% acetonitrile in water gradient with 0.1% trifluoroacetic acidaffordedN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.7 (d, 1), 9.4 (d, 1), 8.3 (m, 1), 8.2 (d, 1), 8.1 (d, 1), 7.8 (d,1), 7.7 (d, 1), 7.3 (d, 1), 7.2 (d, 1), 4.6 (d, 2), 3.9 (s, 3), 3.6 (m,2), 2.9˜3.2 (m, 5), 2.2 (m, 2) ppm.

C. Sodium hydride (60%, 0.1 g, 2.5 mmol) was added in portions to amixture of ethyl (2-trifluoroethyl)acetimidate hydrochloride (0.53 g,2.5 mmol) and DMF (4 mL), and stirred at 0° C. for 5 minutes, then atambient temperature for 20 minutes. The mixture was re-cooled to 0° C.,andN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.25 g, 0.5 mmol) was added. After stirring at ambient temperature for15 hours, cesium carbonate (0.6 g, 1.8 mmol) was added and the stirringwas continued for 5 days. The mixture was cooled in an ice bath, andtrifluoroacetic acid (0.5 mL) was added dropwise. Purification by HPLCon a C18 Dynamax column with 20-70% acetonitrile in water gradient with0.1% trifluoroacetic acid gave 0.15 g ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-imino-4,4,4-trifluorobutyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a white solid; NMR (DMSO-d₆ /TFA) 10.90(s, 1), 9.3-9.4 (m, 2), 8.90 (d, 1), 8.30 (m, 1), 8.10 (d, 1), 7.75-7.85(m, 2), 7.30 (s, 1), 7.25 (s, 1), 4.70 (s, 0.8), 4.60 (s, 1.2), 3.80 (s,1), 3.20 (s, 1.8), 3.00 (s, 1.2), 2.90 (m, 2), 2.60 (m, 2) ppm.

D. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(3-cyano-1-iminopropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.90 (s, 1H), 9.90 (s, 1H),9.70 (s, 1H), 9.40 (s, 1H), 8.40 (d, 1H), 8.10 (d, 1H), 7.90 (dd, 1H),7.80 (s, 1H), 7.40 (d, 1H), 7.25 (d, 1H), 4.80 (s, 2H), 3.90 (s, 3H),3.55 (q, 2H), 3.20-3.10 (m, 2H), 3.00-2.90 (m, 2H), 1.20 (t, 3H) ppm;and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-imino-4,4,4-trifluorobutyl)amino)methyl)-3-chlorothlophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.85 (s, 1), 9.90 (b, 1),9.40 (b, 1), 9.35 (s, 1), 9.00 (b, 1), 8.28 (d, 1), 8.08 (d, 1), 7.85(s, 1), 7.80 (dd, 1), 7.25 (d, 1), 4.40 (d, 2), 3.80 (s, 3), 2.60-2.70(m, 4)

E. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 9

Compounds of Formula (Io)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(1.0 g, 2.1 mmol) in THF (30 mL) at 0° C. was added2-bromoethylisocyanate (0.24 mL, 2.6 mmol) and the mixture stirred atambient temperature. After 7 hours, an additional 0.12 mL (1.3 mmol) of2-bromoethylisocyanate was added. After a further 16 h, the mixture wascooled to 0° C. and triethylamine (0.60 mL, 4.3 mmol) was added. Thereaction mixture was warmed slowly to ambient temperature and stirredfor 24 hours, then concentrated of all volatiles in vacuo. The resultinggum was dissolved in ethyl acetate (50 mL), washed with brine (50 mL),dried over MgSO₄ and concentrated in vacuo. Purification by flashchromatography on silica gel afforded 0.77 g (67%) ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;as a white foam; NMR (CDCl₃) 11.2 (s, 1), 8.7 (s, 1), 8.6 (d, 1),7.4-8.3 (m, 6), 4.4 (s, 2), 4.4 (t, 2), 3.8 (t, 2), 3.0 (s, 3) ppm.

B. In a similar manner, the following compounds were made: days, then itwas poured into water. The resulting mixture was extracted with CH₂ Cl₂(2×50 mL). The organic layer was washed with 1% K₂ CO₃, brine, treatedwith charcoal and concentrated. Purification by silica gelchromatography using 10:1 CH₂ Cl₂ :CH₃ OH with 1% NH₄ OH followed byprecipitation from CH₂ Cl₂ and hexane affordedN-(5-chloropyridin-2-yl)-2-[((4-(((diethylamino)oxy)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white solid; NMR (DMSO-d₆) 8.35 (s, 1H), 8.20 (s, 1H), 8.10 (d,1H), 7.90 (dd, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 4.20 (s, 2H), 3.85 (s,3H), 3.20-2.80 (m, 4H), 1.20 (t, 6H) ppm.

M. In a similar manner, the following compound was made:

N-(5-chloropyridin-2-yl)-2-[((4-((3-amino-1,2,4-triazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s., 1), 8.4 (d, 1), 8.3 (m, 2), 8.1(d, 1), 7.9 (dd, 1), 7.7 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 5.1 (s, 2), 3.9(s, 3) ppm.

N. In a manner similar to that described above in Paragraph F, to asolution of 2-methyl-4,5-dihydroimidazole (1.50 g, 17.8 mmol),N,N-diethylhydroxylamine (0.45 g, 5.0 mmol),N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(2.00 g, 4 mmol) and DMF (15 mL) was added K₂ CO₃ (2.50 g, 18.1 mmol).The mixture was stirred at ambient temperature for 16 hours.Purification by HPLC on a C18 Dynamax column with 20-50% acetonitrile inwater gradient with 0.1% trifluoroacetic acid afforded thetrifluoroacetic acid salt ofN-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 10.2 (s, 1), 9.4 (s, 1), 8.3 (s, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8 (d,1), 7.3 (s, 1), 7.2 (s, 1), 4.6 (s, 2), 3.8 (s, 3), 3.7 (s, 4), 2.3 (s,3) ppm.

O. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((4-amino-5-(aminocarbonyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.8 (s, 1), 8.4 (d, 1), 8.1 (dd, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.4 (d,1), 7.3 (d, 1), 5.3 (s, 2), 3.9 (s, 3) ppm; and

N-(5-chloropyridin-2-yl)-2-[((4-((2-iminopiperidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.3 (d, 1),9.1 (s, 1), 8.6 (br s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.6 (d,1), 7.4 (d, 1), 7.3 (d, 1), 4.6 (s, 2), 3.9 (s, 3), 3.4 (m, 2), 2.7 (m,2), 1.9 (m, 4) ppm.

P. In a similar manner to that described in Paragraph F above, to asolution of theobromine (1.06 g, 5.9 mmol), N,N-diethylhydroxylamine(0.45 g, 5.0 mmol),N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.32 g, 0.6 mmol), and DMF (40 mL) was added K₂ CO₃ (0.74 g, 5.3 mmol).The mixture was stirred at 40° C. for 6 days, then it was poured intowater. The solid was isolated by filtration. Purification byrecrystallization from CH₂ Cl₂ and CH₃ OH affordedN-(5-chloropyridin-2-yl)-2-[((4-((2,3,4,5,6,7-hexahydro-3,7-dimethyl-2,6-dioxo-1H-purin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white solid; NMR (DMSO-d₆) 10.90 (s, 1H), 9.40 (s, 1H), 8.36 (d,1H), 8.12 (d, 1H), 8.06 (s, 1H), 7.90 (dd, 1H), 7.55 (s, 1H), 7.38 (d,1H), 7.27 (d, 1H), 4.97 (s, 2H), 3.90 (s, 6H), 3.40 (s, 3H) ppm.

Q. In a manner similar to that described in Paragraph P above, a mixtureof cytosine (0.3 g, 3.0 mmol),N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.25 g, 0.5 mmol), cesium carbonate (0.5 g, 1.5 mmol), and DMF (5 mL)was heated under N₂ at 60° C. for 15 hours. The mixture was cooled inice bath, and trifluoroacetic acid (0.5 mL) was added dropwise.Purification by HPLC on a C18 Dynamax column with 20-70% acetonitrile inwater gradient with 0.1% trifluoroacetic acid gave 0.17 g of thetrifluoroacetic acid salt ofN-(5-chloropyridin-2-yl)-2-[((4-((5-amino-2-oxo-2H-pyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a white solid; NMR (DMSO-d₆, 40° C.) 10.75(s, 1), 9.35 (s, 1), 9.30 (b, 1), 8.35 (b, 1), 8.30 (d, 1), 8.05 (d, 1),7.95 (d, 1), 7.85 (dd, 1), 7.90 (s, 1), 7.35 (d, 1), 7.25 (d, 1), 6.00(d, 1), 4.90 (s, 2), 3.85 (s, 3) ppm.

R. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((6-aminopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, andN-(5-chloropyridin-2-yl)-2-[((4-((6-aminopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.75 (s, 0.5), 10.74 (s,0.5), 9.35 (m, 1.5), 8.83 (s, 0.5), 8.82 (b, 0.5), 8.55 (s, 0.5), 8.30(m, 1.5), 8.27 (s, 0.5), 8.12 (b, 1), 8.06 (d, 1), 7.86 (m, 1, 5), 7.70(s, 1), 7.34 (t, 1), 7.25 (t, 1), 5.56 (s, 1), 5.35 (s, 1), 3.80 (s, 3)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-6-oxopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, andN-(5-chloropyridin-2-yl)-2-[((4-((2-amino-6-oxopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.75 (s, 1), 10.65 (s, 0.5),9.33 (s, 1), 8.38 (s, 0.5), 8.31 (t, 1), 8.06 (dd, 1), 7.91 (s, 0.5),7.88 (dd, 0.5), 7.86 (dd, 0.5), 7.69 (s, 0.5), 7.50 (s, 0.5), 7.34 (d,1), 7.25 (d, 1), 6.75 (b, 1), 6.50 (b, 1), 5.40 (s, 1), 5.10 (s, 1),3.85 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-4-imino-1,4-dihydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.80 (s, 1), 9.35 (s, 1),8.33 (d, 1), 8.22 (s, 1), 8.10 (s, 1), 8.07 (d, 1), 8.10 (s, 2), 7.88(dd, 1), 7.72 (d, 1), 7.65 (s, 1), 7.36 (d, 1), 7.26 (d, 1), 6.40 (d,1), 5.00 (s, 2), 3.85 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(imino(thiophen-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.85 (s, 1), 10.10 (s,1), 9.60 (s, 1), 9.40 (s, 1), 9.20 (s, 1), 8.29 (d, 1), 8.10 (d, 1),8.00 (dd, 1), 7.91 (dd, 1), 7.84 (s, 1), 7.82 (dd, 1), 7.30 (d, 1), 7.26(m, 2), 4.55 (d, 2), 3.80 (s, 3) ppm; and

N-(5-chloropyridin-2-yl)-2-[((4-((2,4-diamino-6-hydroxypyrimidin-5-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.85 (s, 1), 9.30 (s, 1),8.30 (d, 1), 8.10 (d, 1), 8.00 (b, 1), 7.80 (dd, 1), 7.35 (s, 1), 7.30(s, 1), 7.25 (s, 1), 3.80 (s, 3), 3.40 (s, 2) ppm.

S. In a manner similar to that described in Paragraph D, to a solutionof benzamidine hydrochloride (0.78 mg, 5 mmol) and DMF (10 mL) was addedNaH (0.21 g, 5.2 mmol). The mixture was stirred at ambient temperaturefor 30 minutes. The mixture was cooled to 0° C., thenN,N-diethylhydroxylamine (0.45 g, 5.0 mmol),N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.51 mg, 1 mmol) was added. The mixture was allowed to warm to ambienttemperature and stirred for 5 days. The mixture was added to water andthe resulting precipitate was isolated by filtration. Purification byHPLC on a C18 Dynamax column with 25-95% acetonitrile in water gradientwith 0.1% trifluoroacetic acid afforded the trifluoroacetic acid salt ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-(imino(phenyl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.90 (s, 1H), 10.10 (br s, 1H), 9.65 (br s, 1H), 9.40 (s,1H), 9.25 (br s, 1H), 8.40 (d, 1H), 9.10 (d, 1H), 7.95 (s, 1H), 7.90(dd, 1H), 7.80-7.70 (m, 3H), 7.65-7.59 (m, 2H), 7.40 (d, 1 H), 7.30 (d,1H), 4.55 (s, 2H), 3.85 (s, 3H) ppm.

T. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-imino-2-(aminocarbonyl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.90 (s, 1H), 9.40 (s, 1H),8.90 (s, 2H), 8.70 (s, 2H), 8.40 (d, 1H), 8.10 (d, 1H), 7.90 (dd, 1H),7.70 (s, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.40 (s, 1H), 7.25 (s, 1H),3.90 (s, 3H), 3, 80 (m, 2H), 3.20 (m, 2H) ppm; and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(cyclopropyl(imino)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.90 (s, 1H), 8.60 (br s, 1H),9.38 (s, 1H), 8.70 (br s,1H), 8.38 (d, 1H), 8.10 (d, 1H), 8.00-7.80 (m,2H), 7.40 (d, 1H), 7.25 (d, 1H), 4.40 (s, 2H), 3.90 (s, 3H), 1.98-1.85(m, 1H), 1.20-1.10 (m, 4H) ppm.

U. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 4 Compounds of Formula (If)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.3 g, 2.5 mmol) in pyridine (20 mL) at 0° C. was added methanesulfonylchloride (0.20 mL, 2.8 mmol). The solution was allowed to warm toambient temperature with stirring. After 16 hours, the pyridine wasremoved in vacuo. The resulting oil was purified by flash chromatographyon silica gel to afford 1.1 g (75% yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.3 (s,1), 8.1 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 4.2 (s,2), 3.9 (s, 3), 3.0 (s, 3), 2.7 (s, 3) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methylsulfonyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1), 7.3-8.5 (m, 6), 4.3 (s, 2),2.8-4.1 (m, 14), 2.5 (s, 3), 2.2-2.5 (m, 2), 1.0-1.2 (m, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.4 (s, 1), 8.1 (d, 1), 7.9(d, 1), 7.8 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 4.3 (s, 2), 3.9 (s, 3), 2.8(s, 6), 2.7 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((3,5-dimethylisoxazol-4-yl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.4 (s, 1), 8.1 (d, 1), 7.9(d, 1), 7.8 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 4.3 (s, 2), 3.9 (s, 3), 2.7(s, 3), 2.6 (s, 3), 2.4 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(methyl)sulfonyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1), 9.4 (s, 1), 8.4 (s, 1), 8.1(d, 1), 7.9 (s, 1), 7.9 (d, 1), 7.4 (s, 1), 7.3 (s, 1), 4.2 (s, 2) 3.9(s, 3), 3.6 (m, 2), 3.2 (m, 2), 3.1 (s, 3), 2.8 (s, 6) ppm; and

N-(5-chloropyridin-2-yl)-2-[((4-((((2-chloroethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

C. In a similar manner to that described in Paragraph A above,N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide(0.7 g, 1.2 mmol) reacted with methanesulfonyl chloride (0.1 mL, 1.3mmol) to affordN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide.Purification by HPLC on a C18 Dynamax column with 20-80% acetonitrile inwater gradient with 0.1% trifluoroacetic acid afforded thetrifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.5 (s, 1), 8.4 (d, 1), 8.2 (d, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.4 (d,2), 4.3 (s, 2), 3.4 (d, 2), 3.0 (s, 2), 2.9 (s, 3), 2.7 (s, 3), 2.4 (brs, 3), 2.2 (s, 4) ppm.

D. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 9.8 (s, 1), 7.3-8.7 (m,6), 3.9 (s, 2), 4.3 (s, 2), 3.8-4.0 (m, 4), 2.8-3.0 (m, 4), 2.9 (s, 3)ppm.

E. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 5 Compounds of Formula (Ig)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.0 mmol) in dioxane (20 mL) was added ethyl isocyanate (0.18mL, 2.2 mmol) and the reaction stirred at ambient temperature. After 16hours, the mixture was concentrated of all volatiles in vacuo. Theresidual solid was purified by flash chromatography on silica gel toafford 0.85 g (74% yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.4 (s,1), 8.1 (d, 1), 7.9 (d, 1), 7.5 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 4.4 (s,2), 3.9 (s, 3), 3.1 (q, 2), 2.8 (s, 3), 1.0 (t, 3) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1), 9.5 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9 (dd,1), 7.5 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 6.4 (t, 1), 4.3 (s, 2), 3.3 (m,4), 3.1 (m, 2), 2.9 (m, 4), 2.8 (s, 3), 1.4 (s, 9), 1.0 (t, 3) ppm.

C. In a manner similar to that described in Paragraph A above,N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.0 mmol) reacted with morpholinoethyl isothiocyanate (0.34 g,2.0 mmol) in THF (20 mL) to affordN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-(morpholin-4-yl)ethyl)thioureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.Purification by HPLC on a C18 Dynamax column with acetonitrile in watergradient with 0.1% trifluoroacetic acid afforded the trifluoroaceticacid salt as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.7 (br s,1), 9.3 (s, 1), 7.2-8.3 (m, 7), 4.9 (s, 2), 3.9 (t, 4), 3.8 (s, 3), 3.7(t, 2), 3.5 (d, 2), 3.3 (br, 2), 3.2 (br, 5) ppm.

D. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N"-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (d, 1), 9.6 (d, 1),7.3-8.5 (m, 6), 2.9-4.5 (m, 12), 2.8 (s, 3), 2.4 (br d, 2), 1.7-2.0 (m,4) ppm.

E. A solution of potassium cyanate (0.70 g, 8.6 mmol) in methanol (4 mL)was added dropwise to a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.10 g, 0.20 mmol) in acetic acid (1.5 mL), and the mixture was stirredat ambient temperature for 20 hours. Concentration and purification byHPLC on a C18 Dynamax column with 20-70% acetonitrile in water gradientwith 0.1% trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-((N'-methylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (brs, 1), 9.3 (s, 1), 8.2 (s, 1), 8.1 (s, 1), 7.8 (d, 1), 7.5 (s, 1), 7.2(s, 2), 4.4 (s, 2), 3.8 (s, 3), 2.9 (s, 3) ppm.

F. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-hydroxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (CDCl₃) 9.7 (br s, 1), 9.0 (s, 1), 8.3 (d, 1), 8.0 (d, 1), 7.7 (dd,1), 7.4 (s, 1), 7.2 (d, 1), 7.0 (s, 1), 5.8 (br s, 2), 4.4 (s, 2), 3.9(s, 3), 3.8 (br s, 1), 3.7 (t, 2), 3.4 (t, 2) ppm.

G. To a solution of bis(trichloromethyl) carbonate (0.15 g, 0.51 mmol)in CH₂ Cl₂ (5 mL) at 0° C. was addedN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.10 g, 0.20 mmol), and the mixture stirred for 0.5 hour. Ethanolamine(0.40 mL, 6.6 mmol) was then added and the mixture was stirred atambient temperature for 4 hours. Concentration in vacuo and purificationby HPLC on a C18 Dynamax column with 20-70% acetonitrile in watergradient with 0.1% trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-hydroxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (brs, 1), 9.3 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.7 (br s, 1),7.5 (s, 1), 7.3 (s, 1), 7.2 (s, 1), 4.4 (s, 2), 3.8 (s, 3), 3.4 (t, 2),3.1 (t, 2), 2.8 (s, 3) ppm.

H. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.7 (s, 1),9.3 (s, 1), 7.2-8.3 (m, 6), 4.3 (s, 2), 3.9 (s, 3), 3.0-3.7 (m, 12), 2.7(s, 3) ppm.

I. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.42 g, 0.87 mmol) in dioxane (5 mL) was added ethyl3-isocyanatopropionate (0.15 mL, 1.0 mmol) and the mixture

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(thiazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 10.1 (br d, 1), 9.5 (s, 1), 7.3-8.5 (m,6), 4.7 (m, 2), 4 (m, 2), 3.9 (s, 3), 3.6 (m, 2), 3.2 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.5 (s, 1), 10.3 (m, 1), 9.4 (s, 1), 7.3-8.0 (m, 7), 4.8(m, 2), 4.6 (s, 2), 3.9 (m, 2), 3.8 (s, 3), 3.0 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 10.3 (d, 1), 9.4 (s, 1), 7.3-8.4 (m, 6),4.8 (t, 2), 4.5 (s, 2), 3.9 (t, 2), 3.8 (s; 3), 3.0 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(dihydro-4(H)-1,3-oxazin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1), 9.4 (s, 1), 9.3 (br s, 1), 8.4 (s, 1), 8.1(d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 4.6 (m, 2), 4.5(s, 2), 3.9 (s, 3), 3.4 (m, 4), 2.0 (m, 2), 1.1 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (CDCl₃) 9.0 (s, 1), 8.9 (s, 1), 8.2 (d, 1), 8.1 (d, 1), 7.6 (dd, 1),7.4 (s, 1), 7.3 (d, 1), 7.0 (d, 1), 4.4 (s, 2), 4.3 (t, 2), 3.9 (s, 3),3.8 (t, 2), 3.3 (q, 2), 1.1 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2,2,2-trifluoroethyl)-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.8(d, 1), 7.75 (d, 1), 7.2 (d, 2), 4.9 (t, 2), 4.7 (s, 2), 4.4 (br s, 2),3.9 (t, 2), 3.8 (s, 3) ppm.

C. In a similar manner to that described in Paragraph A above,N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.5 g, 3.0 mmol) reacted with 3-bromopropylisocyanate (0.54 mL, 3.6mmol), followed by triethylamine (2.0 mL, 15 mmol) to affordN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(dihydro-4(H)-1,3-oxazin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.Purification by HPLC on a C18 Dynamax column with acetonitrile in watergradient with 0.1% trifluoroacetic acid afforded the trifluoroaceticacid salt as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),9.3 (br s, 1), 8.4 (s, 1), 8.1 (d, 1), 7.9 (d, 1), 7.9 (s, 1), 7.4 (s,1), 7.3 (s, 1), 4.6 (m, 2), 4.5 (s, 2), 3.9 (s, 3), 3.4 (m, 2), 3.0 (s,3), 2.0 (s, 2) ppm.

D. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 10.3 (d, 1),9.4 (s, 1), 7.2-8.4 (m₁ 6), 4.8 (t, 2), 4.6 (s, 2), 3.9 (t, 2), 3.8 (s,3), 3.7 (br d, 4), 3.0 (s, 3), 2.9 (br d, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(thiazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 10.1 (br d,1), 9.4 (d, 1), 7.2-8.4 (m, 6), 4.7 (d, 2), 4.0 (q, 2), 3.9 (s, 3),3.4-3.7 (m, 4), 1.0-1.2 (m, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-(oxo)oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 10.5 (s, 1),9.4 (d, 1), 7.3-8.4 (m, 6), 4.5-4.8 (m, 4), 3.9 (s, 3), 3.4-3.7 (m, 4),3.0 (d, 3) ppm;

N-(4-chlorophenyl)-2-[((4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.5 (s, 1), 10.3 (d, 1),9.6 (s, 1), 7.3-8.1 (m, 7), 4.9 (t, 2), 4.6 (s, 2), 3.9 (t, 2), 3.7 (brd, 4), 3.0 (s, 3), 2.9 (br d, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 10.3 (s, 1),9.5 (s, 1), 7.3-8.1 (m, 6), 4.9 (m, 2), 4.6 (s, 2), 3.9 (m, 2), 3.7 (m,4), 3.4 (m, 2), 2.9 (m, 4), 1.0 (m, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(t-butyl)-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.5 (s, 1), 7.4 (d, 1), 7.2 (d, 1),4.4 (s, 2), 4.1 (t, 2), 3.9 (s, 3), 3.6 (t, 2), 1.4 (s, 9) ppm;

5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.4 (s, 1), 10.0 (s, 1),9.2 (s, 1), 6.5-7.4 (m, 6), 5.2 (s, 2), 3.8 (t, 2), 3.6 (s, 2), 2.8 (t,2), 2.0 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-methoxyethyl)-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 10.3 (d, 1),9.4 (s, 1), 7.2-8.4(m, 6), 4.8 (m, 2), 4.6 (s, 2), 3.9 (s, 6), 3.5 (s,2), 3.4 (s, 2), 3.2 (d, 2) ppm;

5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N'-(2-methoxyethyl)-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.5 (d, 1), 11.0 (s, 1),10.3 (d, 1), 7.5-8.4 (m, 6), 6.1 (s, 2), 4.8 (s, 2), 4.6 (s, 2), 3.9 (m,3), 3.4-3.6 (m, 4), 3.2 (d, 2) ppm.

E. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 10 Compounds of Formula (Iq)

A. A mixture ofN-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide(2.1 g, 3.7 mmol) and cesium carbonate (8 g, 25 mmol) in dimethylformamide (50 mL) was stirred at ambient temperature for 1.0 hour. Asolution of 1-chloro-3-iodopropane (1.1 g, 5.6 mmol) in dimethylformamide (1.5 mL) was added dropwise, and stirring continued for 18hours. 2-(methylamino)ethanol (1.5 mL, 18.7 mmol) was then added, andthe mixture was heated at 65° C. for 12 hours. After cooling to ambienttemperature the mixture was filtered, and the filtrate was acidifiedwith trifluoroacetic acid. Purification by HPLC on a C18 Dynamax columnwith 20-70% acetonitrile in water gradient with 0.1% trifluoroaceticacid affordedN-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(N'-methyl-N'-(2-hydroxyethyl)amino)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt as tan solid; NMR (DMSO-d₆ /TFA) 11.0 (s, 1),9.6 (s, 1), 9.4 (br, m, 1), 8.3 (s, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (d,1), 7.4 (s, 1), 7.3(s, 1), 4.4(s, 2), 4.2 (br t, 2), 3.0-4.0 (m, 14),2.9 (s, 3), 2.8 (s, 3), 2.1 (m, 2) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-morpholinylpropoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.9 (br s,1), 9.6 (s, 1), 8.4 (d, 10), 8.2 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.4(s, 1), 7.3 (s, 1), 4.4 (s, 2), 4.2 (t, 2), 3.9 (d, 2), 3.3-3.8 (m, 12),3.3 (t, 2), 2.9-3.1 (m, 2), 2.9 (s, 3), 2.1 (m, 2) ppm;

N-5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.6 (s, 1),8.4. (d, 1), 8.2 (s, 1), 8.15 (d, 1), 7.9 (dd, 1), 7.4 (s, 1), 7.3 (s,1), 4.4 (s, 2), 4.2 (t, 2), 3.2-3.8 (m, 12), 3.0 (m, 2), 2.9 (s, 3), 2.1(m, 2), 1.9 (m, 2), 1.8 (m, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-methylpiperidin4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.9 (br s,1), 9.8 (br m, 1), 9.6 (s, 1), 8.4 (d, 1), 8.2(s, 1), 8.1 (d, 1), 7.8(dd, 1), 7.4 (s, 1), 7.3 (s, 1), 4.4 (br m, 2), 4.2 (t, 2), 3.9 (d, 2),3.5-3.7 (m, 5), 3.4 (d, 2), 3.3 (t, 2), 3.0 (m, 4), 2.8 (s, 3), 2.7 (s,3), 2.3 (m, 2), 2.1 (m, 2), 2.0 (br q, 2) ppm;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.6 (s, 1), 9.9 (br m,1), 9.7 (s, 1), 8.2 (s, 1), 7.7 (d, 2), 7.4 (s, 1), 7.4 (s, 1), 7.3 (d,2), 4.4 (s, 2), 4.2 (br t, 2), 3.9 (d, 2), 3.0-3.7 (m, 16), 2.9 (s, 3),2.1 (m, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.7 (br s,2), 9.6 (s, 1), 8.3 (d, 1), 8.2(s, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.4 (s,1), 7.3 (s, 1), 4.3 (br d, 2), 4.2 (t, 2), 3.7 (t, 2), 3.5 (m, 2), 3.3(m, 2), 3.2 (m, 2), 2.9 (m, 2), 2.7 (s, 3), 2.1 (m, 2), 1.9 (m, 2), 1.8(m, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.8 (br s,1), 9.7 (br s, 1), 9.6 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8(dd, 1), 7.4 (s, 1), 7.3 (s, 1), 4.3 (br d, 2), 4.2 (t, 2), 3.9 (d, 2),3.7 (t, 2), 3.6 (t, 2), 3.4 (d, 2), 3.3 (m, 2), 3.2 (m, 2), 3.0 (m, 2),2.7 (s, 3), 2.1 (m, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(imidazol-1-yl)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.7 (s, 1),9.0 (s, 1), 8.4 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.7(s, 1),7.6 (s, 1), 7.3 (s, 2), 4.4 (br m, 4), 4.0 (t, 2), 3.1-3.7 (m, 8), 2.8(s, 3), 2.2 (m, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyt)amino]-3-(3-(imidazol-1-yl)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 10.7 (s, 1),9.1 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.7 (s, 1),7.6 (s, 1), 7.3 (s, 2), 4.2-4.5 (m, 4), 4.0 (t, 2), 3.8 (t, 2), 3.2 (m,2), 2.8 (s, 3), 2.2 (m, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(4-ethylpiperazin-1-yl)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (br s, 1), 9.5 (s,1), 8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.4 (s, 1), 7.3 (s,1), 4.2 (br s, 2), 3.1-3.9 (m, 10), 2.9 (s, 3), 2.7 (s, 3), 2.2 (m, 2),1.2 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyridin-3-yloxy)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 11.0 (s, 1), 9.6 (s, 1),7.9-8.7 (m, 8), 7.4 (d, 2), 4.4 (m, 6), 3.9 (m, 2), 2.8 (s, 3), 2.2 (m,2) ppm.

C. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide(1.3 g, 1.7 mmol) in DMF (30 mL) was added sodium hydride (60%dispersion in mineral oil, 0.16 g, 4.0 mmol), followed after 0.5 hour by2-bromoethyl acetate (0.37 g, 2.2 mmol). The mixture was stirred atambient temperature. After 24 hours NaOH (25% solution in water, 3 mL)was added, and the mixture was stirred for a further 4 hours. Themixture was acidified with trifluoroacetic acid, and purified by HPLC ona C18 Dynamax column with 20-70% acetonitrile in water gradient with0.1% trifluoroacetic acid to affordN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide,trifluoroacetic acid salt as white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.6 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.4 (s,1), 7.3 (s, 1), 4.4 (s, 2), 4.2 (t, 2), 3.7 (t, 2), 3.6 (m, 2), 3.5 (m,2), 3.0-3.8 (br m, 4), 2.8 (s, 3), 2.0 (br s, 4) ppm. Also obtained fromthis reaction wasN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-acetoxyethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.8 (s, 1), 9.4 (s, 1),8.3 (s, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (d, 1), 7.4 (s, 1), 7.3 (s, 1),4.4 (s, 2), 4.3 (s, 4), 3.6 (m, 4), 3.5 (m, 4), 3.1-3.6 (br m, 4), 2.8(s, 3), 1.9 (s, 3) ppm.

D. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 10), 7.8 (dd, 1), 7.4 (s, 1), 7.3 (s,1), 4.4 (s, 2), 4.2 (t, 2), 3.7 (t, 2), 3.1-3.9 (br m, 8), 2.8 (s, 3)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.3 (s, 1), 7.2 (s, 1),4.4 (s, 2), 4.1 (t, 2), 3.7 (t, 2), 3.5 (br s, 4), 2.9 (s, 6), 2.8 (s,3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.6 (s, 1),8.4 (s, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.4 (s, 1), 7.3 (s, 1),4.4 (br, 4), 4.2 (t, 2), 3.9-3.3 (m, 6), 3.2 (s, 3), 2.9 (s, 3), 2.4-2.2(m, 4) ppm.

E. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 11 Compounds of Formula (Ir)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide(1.0 g, 1.8 mmol) in DMF (15 mL) was added sodium hydride (0.051 g, 2.2mmol) and the mixture stirred at ambient temperature. After 0.5 hours,ethyl bromoacetate (0.30 g, 1.8 mmol) was added and stirring continued.After 3 hours, the mixture was cooled to 0° C. and acidified withtrifluoroacetic acid. Purification by HPLC on a C18 Vydac column withacetonitrile in water gradient with 0.1% trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxy-5-chlorobenzamide,trifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.4 (s, 1), 8.4 (dd, 1), 8.1 (d, 1), 8.0 (s, 1), 7.9 (dd, 1), 4.6(s, 2), 4.3 (q, 2), 4.2 (s, 2), 3.8 (s, 4), 3.4 (s, 4), 3.4 (s, 3), 1.2(t, 3) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(methylthio)methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.8 (s, 1), 9.3 (s, 1),8.3 (s, 1), 8.1 (d, 1), 8.1 (s, 1), 7.9 (dd, 1), 7.2 (s, 1), 7.12 (s,1), 4.9 (s, 2), 4.3 (s, 2), 3.6 (s, 4), 3.5 (s, 4), 3.2 (s, 3), 2.4 (s,3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1),8.4 (s, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (br, 1), 7.2 (s, 1), 7.2 (s, 1),4.4 (s, 2), 4.2 (br, 2), 3.7 (br, 2), 3.6 (br, 2), 3.5 (br, 2), 3.3 (s,3), 2.8 (s, 3), 1.9 (br, 4) ppm;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.6 (s, 1/2), 10.5 (s,1), 9.3 (s, 1/2), 7.8 (s, 1), 7.6 (d, 2), 7.4 (d, 2), 7.2 (s, 1), 7.1(s, 1), 4.6 (s, 2), 4.2 (q, 2), 3.6 (s, 2), 3.4 (br, 8), 3.2 (t, 3), 3.1(s, 3) ppm;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((acetoxy)ethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.4 (s, 1), 9.5 (s, 1),7.7 (d, 2), 7.4 (s, 1), 7.2 (d, 2), 7.1 (s, 1), 4.4 (s, 2), 4.4 (s, 4),3.5 (br, 8), 2.9 (s, 3), 1.9 (s, 1) ppm;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(morpholin-4-yl)ethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.6 (s, 1), 9.7 (s, 1),8.2 (s, 1), 7.7 (d, 2), 7.5 (s, 1), 7.4 (s, 1), 7.2 (d, 2), 4.5 (s, 2),4.4 (s, 2), 3.9-3.1 (m, 20), 2.9 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((methylthio)methoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.6 (s, 1), 9.6 (s, 1),8.2 (s, 1), 7.7 (d, 2), 7.5 (s, 1), 7.3 (d, 2), 5.4 (s, 2), 4.4 (s, 2),3.2 (br, 8), 3.9 (s, 3), 2.2 (s, 3) ppm.

C. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide(2.0 g, 3.6 mmol) in DMF (20 mL) were added cesium carbonate (8.0 g, 25mmol) and 2-bromoethyl ethyl ether (0.71 g, 4.6 mmol). The suspensionwas heated at 60° C. for 16 hours. The mixture was cooled to ambienttemperature and filtered, and the filtrate was acidified withtrifluoroacetic acid. Purification by HPLC on a C18 Dynamax columnacetonitrile in water gradient with 0.1% trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-clorothiophen-2-yl)carbonyl)amino]-3-(2-ethoxyethoxy)-5-chlorobenzamidetrifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 11.9 (s,1), 9.4 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.4 (s,1), 7.3 (s, 1), 4.4 (s, 2), 4.2 (t, 2), 3.7 (t, 2), 3.5 (q, 2), 3.5 (br,8), 2.9 (s, 3), 1.0 (t, 3) ppm.

D. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (br s,1), 9.4 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (d, 1), 7.4 (s,1), 7.3 (s, 1), 4.3 (br d, 2), 4.2 (t, 2), 3.7 (t, 2), 3.6 (m, 2), 3.3(s, 3), 3.2 (m, 2), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.4 (s, 1), 7.2 (s, 1),4.5 (s, 2), 4.0 (t, 2), 3.0-3.8 (m, 16), 3.2 (s, 3), 1.2 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-aminoethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.6 (s, 1),8.3 (d, 1), 8.1 (d, 1), 7.9 (br s, 3), 7.8 (dd, 1), 7.8 (s, 1), 7.4 (d,1), 7.3 (s, 1), 4.3 (t, 2), 4.2 (s, 2), 3.2 (m, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.8 (br, 1), 10.3 (br,1), 9.4 (br, 1), 8.3 (s, 1), 8.1 (d, 1), 7.9 (d, 1), 7.8 (d, 1), 7.4 (s,1), 7.3 (s, 1), 4.8-4.4 (m, 3), 4.2 (m, 2), 3.9 (m, 2), 3.7 (m, 2), 3.5(m, 2), 3.4 (m, 2), 3.2 (s, 3), 3.0 (s, 2), 2.8 (s, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(pyrrolidin-1-yl)ethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (br s, 1), 9.6 (br s,2), 8.3(d, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.7 (s, 1), 7.4 (s, 1), 7.3 (s,1), 4.4 (m, 2), 4.2 (s,), 3.6 (m, 4), 3.1 (m, ), 2.9 (s, 3), 2.7 (s, 3),1.9 (m, 2), 1.8 (m, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(imidazol-1-yl)ethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.6 (br s,1), 9.5 (s, 1), 9.0 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (dd,1), 7.7 (s, 1), 7.5 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 4.6 (m, 4), 4.4 (m,1), 4.3 (m, 1), 3.8 (t, 2), 3.2 (m, 2), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(imidazol-1-yl)ethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 10.4 (s, 1),9.0 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.7 (s, 1),7.5 (s, 1), 7.4 (s, 1), 7.3 (d, 1), 4.6 (br, 4), 4.2 (s, 2), 2.9 (s, 3),2.6 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(pyrrolidin-1-yl)ethoxy)-5-chlorobenzamide;trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.6 (s, 1),8.4 (s, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.4 (s, 1), 7.4 (s, 1),4.6 (s, 2), 4.9-3.6 (m, 8), 3.2 (dd, 4), 2.8 (s, 3), 2.0 (s, 3), 1.9(br, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (br s,1), 9.4 (s, 1), 8.4 (s, 1), 8.2 (m, 1), 8.1 (d, 1), 7.9 (d, 1), 7.4 (s,1), 7.3 (s, 1), 4.4 (m, 2), 4.3 (m, 2), 4.0 (m, 1), 3.7 (m, 2), 3.4 (m,2), 3.3 (s, 3), 3.1 (m, 2), 2.8 (brs, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-ethoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (s, 1), 8.1 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.4 (s, 1), 7.3 (s, 1),7.2 (s, 1), 4.24.5 (br, 2), 4.1 (q, 2), 3.7 (m, 2), 3.1 (m, 2), 2.8 (s,3), 1.3 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1),8.4 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.4 (d, 1), 7.3 (d, 1),4.4 (br d, 2), 4.2 (br t, 2), 3.8 (t, 2), 3.6 (br t, 2), 3.2 (s, 3),3.2-3.1 (brm, 4), 1.3 (t, 3) ppm.

E, In a manner similar to that described in Paragraph B above,N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide(7.0 g, 13 mmol) reacted with cesium carbonate (29 g, 89 mmol) and2-bromoethyl methyl ether (2.6 g, 19 mmol) in DMF (100 mL) at 60° C.Purification by flash chromatography on silica gel afforded 4.8 g (62%yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,as a yellow solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.4 (s,1), 8.1 (d, 2), 7.9 (d, 1), 7.4 (s, 1), 7.3 (s, 1), 4.2 (s, 2), 4.2 (br,2), 3.6 (s, 2), 3.8-3.0 (br, 8), 3.2 (s, 3), 2.9 (s, 3) ppm.

F. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s, 1), 8.3 (s, 1), 8.2 (s, 1), 8.1(d, 1), 7.8 (d, 1), 7.4 (s, 1), 7.2 (s, 1), 8.1 (d, 10, 7.8 (d, 1), 7.4(s, 1), 7.2 (s, 1), 4.4 (s, 2), 4.3 (s, 2), 3.6 (s, 2), 3.2 (s, 3),3.8-3.20 (br, 8), 3.2 (q, 2), 1.2 (t, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide;(DMSO-d₆ /TFA) 9.2 (s, 1), 9.0 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.7 (dd,), 7.6 (s, 1), 7.3 (d, 1), 7.1 (d, 1), 4.3 (s, 2), 4.2 (t, 2), 3.9 (t,2), 3.7 (m, 2), 3.5 (m, 2), 3.4 (s, 3), 2.9 (s, 3), 2.85 (s, 3)ppm; and

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxybenzamide.

G. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 12 Compounds of Formula (Is)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2,3-epoxypropoxy)-5-chlorobenzamide(0.20 g, 0.30 mmol) in DMF (20 mL) was added imidazole sodium salt (0.15g, 1.6 mmol) and the mixture stirred at ambient temperature. After 18hours, the mixture was concentrated of all volatiles in vacuo, and theresidue dissolved in acetonitrile, water and trifluoroacetic acid.Purification by HPLC on a C18 Dynamax column with 20-80% acetonitrile inwater gradient with 0.1% trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(imidazol-1-yl)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 11.0 (s,1), 9.6 (s, 1), 9.0 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s,1), 7.6 (d, 2), 7.4 (d, 1), 7.3 (d, 1), 4.4-4.3 (m, 2), 4.25 (brm, 1),4.2 (s, 2), 4.1-4.0 (brm, 2), 2.9 (s, 3), 2.7 (s, 3) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.6 (s, 1),8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.4 (d, 1), 7.3 (d, 1),4.3 (s, 2), 4.2 (br m, 1), 4.1 (br s, 2), 3.5 (br m, 2), 3.3 (br m, 2),3.0 (br m, 2), 2.8 (s, 9), 2.7 (s, 3), 2.0-1.8 (br m, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 9.5 (s, 1),8.3 (d, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.7 (s, 1), 7.4 (d, 1), 7.3 (d, 1),4.2 (s, 2), 4.2 (br m, 1), 4.1 (brs, 2), 3.5 (br m, 2), 3.3 (br m, 2),3.0 (br m, 2), 2.9 (s, 3), 2.7 (s, 3), 2.0-1.8 (br m, 4) ppm.

C. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 13 Compounds of Formula (It)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2,3-epoxypropoxy)-5-chlorobenzamide(0.20 g, 0.30 mmol) in methylene chloride (3 mL) was added methanol (5mL), followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.040g, 0.20 mmol) and the mixture stirred at ambient temperature. After 48hours, the reaction was quenched with aqueous NaHCO₃ solution andextracted with methylene chloride. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. Purification by flash chromatography onsilica gel, followed by precipitation from methylene chloride-hexaneafforded 0.080 g (38% yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-methoxypropoxy)-5-chlorobenzamide,as a pale brown solid: NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.3(d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.4 (s, 1), 7.2 (s, 1), 4.2(s, 2), 4.1-4.0 (br m, 2), 4.0-3.9 (m, 1), 3.4-3.3 (m, 1), 3.2 (s, 3),2.9 (s, 3), 2.7 (s, 3) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 14 Compounds of Formula (Iv)

A. A solution ofN-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-difluorobenzamide(0.045 g, 0.090 mmol) in 1-methylpiperazine (1 mL, 10.0 mmol) was heatedat 85° C. for 15 hours. Concentration and purification by HPLC on a C18Dynamax column with 20-70% acetonitrile in water gradient with 0.1%trifluoroacetic acid affordedN-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-(4-methylpiperazin-1-yl)-5-fluorobenzamide,trifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 12.0 (s,1), 10.4 (s, 1), 9.9 (br s, 1), 8.3 (d, 1), 8.0 (m, 1), 7.9 (m, 1), 7.8(d, 1), 7.7 (d, 2), 7.6 (m, 2), 7.3 (d, 2), 3.7 (d, 2), 3.6 (d, 2), 3.2(m, 4), 2.9 (s, 3) ppm.

B. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4-((3-(4-methylpiperazin-1-yl)propyl)amino)-5-fluorobenzamide;NMR (DMSO-d₆ /TFA) 12.5 (s, 1), 10.2 (s, 1), 8.1 (m, 1), 8.0 (d, 1), 7.9(m, 1), 7.8 (d, 1), 7.7 (d, 2), 7.6 (m, 2), 7.4 (d, 2), 3.2-4.0 (m, 12),2.9 (s, 3), 2.0 (m, 2) ppm;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-(N'-methyl-N'(3-(dimethylamino)propylamino-5-fluorobenzamide;

C. 2-Dimethylaminoethanethiol hydrochloride (1.4 g,10 mmol) was stirredin aqueous Na₂ CO₃ (15% solution, 20 mL) for 0.5 hour. The solution wasextracted with ethyl acetate (40 mL) and the organic layer was driedover Na₂ SO₄, and concentrated in vacuo. To a solution of the residualoil in DMF (1.0 mL) was addedN-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-difluorobenzamide(0.45 g, 0.09 mmol) and mixture was heated at 105° C. After 15 hours,the mixture was cooled to ambient temperature and concentrated in vacuo.Purification by HPLC on a C18 Dynamax column with 20-70% acetonitrile inwater gradient with 0.1 % trifluoroacetic acid affordedN-(4-chlorophenyl)-2-[((3-((2-(dimethylamino)ethyl)thio)benzo[b]thien-2-yl)carbonyl)amino]4-((2-(dimethylamino)ethyl)thio)-5-fluorobenzamide,trifluoroacetic acid salt as tan solid; NMR (DMSO-d₆ /TFA) 11.6 (s, 1),10.7 (s, 1), 9.8 (brs, 1), 9.4 (brs, 1), 8.4 (d, 1), 8.0 (dd, 2), 7.8(d, 1), 7.7 (d, 2), 7.5 (m, 2), 7.4 (d, 2), 3.4 (br m, 4), 3.2 (br m,4), 2.8 (s, 6), 2.6 (s, 6) ppm.

D. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 15 Compounds of Formula (Ip)

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,(4.6 g, 8.0 mmol) in methylene chloride (120 mL) was added borontribromide (1 M solution in methylene chloride, 80 mL, 80 mmol). After18 hours, the mixture was poured slowly onto ice (ca. 300 g). Ethylacetate (300 mL) was added, and the aqueous layer was adjusted to pH 7with saturated aqueous NaHCO₃ solution. The layers were separated andthe aqueous layer further extracted with ethyl acetate (300 mL). Thecombined organics were dried over Na₂ SO₄ and concentrated in vacuo toafford 4.5 g (100% yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide,as a tan solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.3 (s, 1), 8.3 (d, 1),8.1 (d, 1), 7.8 (dd, 1), 7.7 (s, 1), 7.1 (dd, 2), 4.2 (s, 2), 2.9 (s,3), 2.7 (s, 3)ppm.

B. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;NMR(DMSO-d₆) 10.6 (s, 1), 10.4 (s, 1), 9.6 (s, 1), 8.1 (m, 1), 7.9 (m,1), 7.7 (d, 2), 7.6 (m, 2), 7.4 (d, 2), 7.1 (d, 2) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N''-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.0 (br s, 1), 9.4 (brs, 1), 8.3 (s, 1), 8.1 (d, 1),7.9 (dd, 1), 7.8 (s, 1), 7.4 (s, 2), 7.3 (t, 2), 7.1 (s, 1), 7.0 (s, 1)4.6 (t, 2), 3.9 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.8 (s, 1), 9.3 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.8(dd, 1), 7.7 (s, 1), 7.1 (d, 2), 4.2 (s, 2), 2.7 (s, 6), 2.65 (s, 3)ppm;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4,5-dihydroxybenzamide;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-hydroxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-hydroxybenzamide;and

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dihydroxybenzamide.

C. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 16 Compounds of Formula (Ib)

A. To a solution of N-(4-chlorophenyl)-2-amino-5-methylbenzamide (0.11g, 0.42 mmol) in pyridine (5 mL) at 0° C. was added2-chlorocarbonyl-3-chlorobenzo[b]thiophene (0.15 g, 0.64 mmol), and themixture allowed to warm to ambient temperature with stirring. After 16hours, the mixture was poured onto water (5 mL) and the resulting whitesolid collected by filtration and dried in vacuo. Recrystallization fromacetonitrile afforded 0.095 g (50% yield) ofN-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide,as a white crystalline solid; NMR (DMSO-d₆ /TFA) 11.4 (s, 1), 10.7 (s,1), 8.2 (d, 1), 7.4-8.2 (m, 10), 2.4 (s, 3) ppm.

B. In a similar manner, the following compounds were made:

N-(4-bromophenyl)-2-[((3-chlorobenzorb]thien-2-yl)carbonyl)amino]-5-methylbenzamide;NMR (DMSO-d₆ /TFA) 11.3 (s, 1), 10.7 (s, 1), 8.2 (d, 1), 7.4-8.2 (m,10), 2.4 (s, 3) ppm;

N-(4-bromophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.4 (s, 1), 10.8 (s, 1), 8.4 (d, 1), 7.5-8.2 (m, 10)ppm;

N-(4-chlorophenyl)-2-[((3-chloro-6-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.3 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.4-7.9 (m, 9),2.5 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.7 (s,1), 8.4 (d, 1), 7.4-8.0 (m, 10),2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;NMR (DMSO-d₆ /TFA) 11.3 (s, 1), 11.2 (s, 1), 8.4 (d, 1), 7.4-8.2 (m, 9),2.4 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((5-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.0 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.4-7.9 (m, 6),7.0 (d, 2) 2.5 (d, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-fluorobenzamide;NMR (DMSO-d6/TFA) 11.7 (s, 1), 11.2 (s, 1), 8.3 (dd, 1), 8.2 (m, 1), 7.9(m, 1), 8.0 (d, 2), 7.7 (d, 1), 7.6 (m, 1), 7.5 (dt, 1), 7.4 (d, 2) ppm;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)aminol-4-methylbenzamide;NMR (DMSO-d₆ /TFA) 11.6 (s, 1), 10.6 (s, 1), 8.2 (s, 1), 8.1 (dd, 1),7.9 (dd, 1), 7.8 (d, 1), 7.7 (d, 2), 7.6 (s, 1), 7.5 (d, 1), 7.4 (d, 2),7.1 (d, 1), 2.4 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methyl-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.6 (s, 1), 10.2 (s, 1), 8.1 (dd, 1), 7.9 (dd, 1),7.7 (d, 2), 7.6-7.5 (m, 4), 7.4 (d, 2), 2.4 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 11.4 (s, 1), 10.8 (s, 1), 8.4 (d, 1), 7.4-8.1 (m, 10)ppm;

N-(4-chlorophenyl)-2-[((3-methoxybenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;NMR (DMSO-d₆) 11.4 (s, 1), 10.7 (s, 1), 8.4 (d, 1), 8.0 (m, 2), 7.8 (d,2), 7.6 (s, 1), 7.4 (m, 5), 4.2 (s, 3), 2.3 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]benzamide;NMR (DMSO-d₆) 11.4 (s, 1), 10.7 (s, 1), 8.4 (d, 2), 8.1 (m, 1), 7.9 (m,1), 7.9 (d, 1), 7.8 (d, 2), 7.6 (m, 3), 7.4 (d, 2), 7.3 (t, 1) ppm;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4,5-difluorobenzamide;NMR (DMSO-d₆) 11.6 (s, 1), 10.7 (s, 1), 8.4 (dd, 1), 8.1 (m, 2), 8.0 (d,1), 7.8 (d, 2), 7.6 (m, 2), 7.4 (d, 2) ppm;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.5 (s, 1), 9.8 (s, 1), 8.1 (m, 1), 7.9 (m, 1), 7.7 (d,2), 7.6 (m, 2), 7.4 (s, 1), 7.4 (d, 2), 7.3 (s, 1), 3.9 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-fluoro-5-chlorobenzamide;NMR (DMSO-d₆) 11.7 (s, 1), 10.8 (s, 1), 8.4 (d, 1), 8.2 (m, 2), 8.0 (d,1), 7.7 (d, 2), 7.6 (m, 2), 7.4 (d, 2) ppm;

N-(4-chlorophenyl)-2-[((3-methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(pyridin-3-yl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(2,4-difluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(pyridin-2-yl)-2-[((3-chlorobenzob]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-methoxyphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(3-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(3-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(3-methylphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chloro-2-methylphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-cyanophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-fluorophenyl)-2-[((benzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-fluorophenyl)-2-[((3-chlorothiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-fluorophenyl)-2-[((3-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-(methylsulfonyl)thiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chlorothiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-methoxybenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-bromothiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-4-((l-methylethyl)sulfonyl)thiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((4-bromo-3-methoxythiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-methoxythiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]benzamide;

N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methoxybenzamide;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4-(trifluoro)methylbenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(4-methylpiperazin-1-yl)benzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-hydroxybenzamide;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-dimethoxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-chlorobenzamide;

N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-fluorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-6-fluorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dimethoxybenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4-methyl-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methylbenzamide;

N-(5-chloropyridin-2-yl)-2-[((4-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.8 (s, 1), 9.3 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.8(dd, 1), 7.5 (d, 1), 7.3 (dd, 2), 3.9 (s, 3), 2.2 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-cyano-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((5-nitro-3-methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((4-nitro-3-methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-3-[((3-chlorobenzo;b]thien-2-yl)carbonyl)amino]pyridin-2-amide;

N-phenyl-2-[((1-bromonaphth-2-yl)carbonyl)amino]-5-methylbenzamide; NMR(DMSO-d₆) 10.9 (s,1), 10.4 (s, 1), 8.26 (d, 1), 8.16 (d, 1), 8.06 (t,2), 7.76 (m, 1), 7.6-7.7 (m, 5), 7.46 (d, 1), 7.30 (t, 2), 7.07 (t, 1),2.4 (s, 3);

N-phenyl-2-[((naphth-2-yl)carbonyl)amino]-5-methylbenzamide; NMR(DMSO-d₆) 11.45 (s, 1), 10.6 (s, 1), 8.5 (s, 1), 8.25 (d, 1), 8.05 (d,2), 8.0 (d, 1), 7.95 (d, 1), 7.75 (m, 3), 7.6 (m, 2), 7.4 (m, 3), 2.4(s, 3).

N-(4-chlorophenyl)-3-[((3-chlorobenzob]thien-2-yl)carbonyl)amino]pyridin-4-amide; NMR (DMSO-d₆) 11.1 (s, 1),10.9 (s, 1), 9.4 (s, 1), 8.6 (d,₁), 8.2 (d, 1), 8.0 (d, 1), 7.8 (m, 3),7.6 (m, 2), 7.4 (d, 2) ppm.

C. A suspension of2-carboxy-3-chloro-4-(4-methylpiperazin-1-yl)methylthiophene HCl salt(2.0 g, 5.8 mmol) in thionyl chloride (50 mL) was heated at reflux.After 90 hours, the mixture was cooled to ambient temperature andconcentrated of all volatiles in vacuo. To a suspension of the resultingsolid in pyridine (20 mL) at 0° C was addedN-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (1.5 g, 5.2 mmol) inpyridine (5 mL). The mixture was stirred and allowed to warm graduallyto ambient temperature. After 16 hours, the mixture was concentrated ofall volatiles in vacuo. Purification by flash chromatography on silicagel afforded 2.2 g (80% yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,as a tan foam; NMR (DMSO-d₆ /TFA) 11.4 (s, 1), 11.0 (s, 1), 7.6-8.4 (m,7), 4.4 (s, 2), 3.04.0 (br m, 8), 2.9 (s, 3) ppm.

D. In a similar manner, the following compounds were made:

N-(5-bromopyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ / TFA) 11.4 (s, 1), 11.0 (s, 1), 7.6-8.5 (m, 7), 4.4 (s,2), 3.0-3.8 (br s, 8), 2.9 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-5-methyl-4-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro4-methyl-5-((4-methylpiperazin-1-yl)methyl)thiophen-2-5yl)carbonyl)amino]-5-chlorobenzamide; and

N-(4-chlorophenyl)-2-[((3-chloro-4-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.8 (s,1), 7.6 (m, 3), 7.4 (d, 2), 3.5 (s, 2), 2.6 (m, 8) ppm.

E. To a mixture of sodium 3-chloro-4-(morpholin-4-yl)methyl-2-thiophenecarboxylate (1.0 g, 3.9 mmol) andN-(4-chlorophenyl)-2-amino-5-chlorobenzamide (0.88 g, 3.1 mmol) inpyridine (20 mL) at -10° C. was added POCl₃ (0.40 mL, 4.3 mmol). After45 minutes, the mixture was poured onto ice-water and the resultingsolid collected by filtration.

Crystallization from 1-butanol afforded 0.26 g (13% yield) ofN-(4-chlorophenyl)-2-[((4-(morpholin-4-yl)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,as a tan solid; NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9(s, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (d, 2), 7.4 (d, 3), 3.6 (s, 2), 3.3(br, 4), 2.4 (br, 4) ppm.

F. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-[((4-(methylamino)sulfonyl-3-methylthiophen-2-yl)carbonyl)amino]-5-methylbenzamide;and

N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)sulfonyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.

G. To a solution of2-chlorocarbonyl-3-chloro4-(2-(N-methyl-N-tert-butoxycarbonylamino)ethyl)thiophene(0.095 g, 0.28 mmol) in methylene chloride (10 mL) was added pyridine(0.056 mL, 0.56 mmol) andN-(5-chloropyridin-2-yl)-2-amino-3-methoxy-5-chlorobenzamide (0.096 g,0.31 mmol) and the mixture was stirred at ambient temperature. After 4days at ambient temperature, the reaction mixture was concentrated invacuo and dissolved in methylene chloride. Trifluoroacetic acid wasadded and the reaction mixture was stirred for 2 days at ambienttemperature. The reaction was quenched with saturated aqueous NaHCO₃solution and extracted with methylene chloride. The combined extractswere dried over Na₂ SO₄, filtered, and concentrated in vacuo. Theproduct was purified by HPLC on a C18 Dynamax column with 25-95%acetonitrile in water gradient with 0.1% trifluoroacetic acid to afford0.054 g ofN-(5-chloropyridin-2-yl)-2-[((4-(2-methylaminoethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.3 (s, 1), 8.4 (br s, 2), 8.2 (s, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.6(s, 1), 7.2 (s, 2), 3.8 (s, 3), 3.1 (brs, 2), 2.9 (m, 2), 2.5 (d, 3)ppm.

H. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 17

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide(0.20 g, 0.37 mmol) in methylene chloride (5 mL) were added potassiumcarbonate (0.10 g, 0.74 mmol) and cyanogen bromide (5.0 M inacetonitrile, 0.10 mL, 0.50 mmol) and the mixture stirred at ambienttemperature. After 2 hours, water (10 mL) was added and the mixtureextracted with ethyl acetate (3×20 mL). The combined organics werewashed with brine (10 mL), dried over Na₂ SO₄, and concentrated invacuo. Purification by flash chromatography on silica gel afforded 0.1 gofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-cyanoamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide.The resulting product material was dissolved in toluene (10 mL), andsodium azide (0.058 g, 0.88 mmol) and tributyltin chloride (0.29 g, 0.88mmol) were added. The mixture was heated at reflux for 2 hours, thencooled to ambient temperature and poured onto brine (10 mL). The mixturewas extracted with ethyl acetate (3×20 mL) and the combined organicswashed with brine (10 mL), dried over Na₂ SO₄, and concentrated invacuo. Purification by HPLC on a C18 Dynamax column with 20-80%acetonitrile in water gradient with 0.1 % trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(tetrazol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.5 (s, 1), 8.3 (s, 1), 8.1 (m, 1), 7.9 (m, 1), 7.7 (s, 1), 7.4 (m,2), 4.6 (s, 2), 3.7 (m, 4), 3.0 (s, 3), 2.9 (m, 4) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(tetrazol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.3 (s, 1),8.3 (s, 1), 8.0 (m, 1), 7.8 (m, 1), 7.6 (s, 1), 7.2 (m, 2), 4.5 (s, 2),3.8 (s, 3), 3.0 (s, 3) ppm.

C. In a manner similar to that described in Paragraph A above,N-(5-chloropyridin-2-yl)-2-[((4-((ethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.60 g, 1.2 mmol) reacted with cyanogen bromide (5 M in acetonitrile,0.6 mL, 3.0 mmol) and potassium carbonate (0.56 g, 4.0 mmol) in CH₂ Cl₂to affordN-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-cyanoamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.This material reacted with sodium azide (0.25 g, 3.8 mmol) andtributyltin chloride (1.3 g, 3.9 mmol) in toluene. Purification by flashchromatography on silica gel afforded 0.37 g (53% yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-(tetrazol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.3 (s, 1), 8.1 (m, 1), 7.9(m, 1), 7.6 (s, 1), 7.2-7.4 (m, 2), 4.5 (s, 2), 4.0 (m, 2), 3.9 (s, 3),1.1 (m, 3) ppm.

D. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 18

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide(0.29 g, 0.50 mmol ) in MeOH were added cyanogen bromide (5 M inacetonitrile, 0.1 mL, 0.5 mmol) and K₂ CO₃ (0.5 g, 3.6 mmol) and thereaction was stirred at ambient temperature. After 1 hour, the mixturewas poured onto ethyl acetate and H₂ O, and the layers separated. Theorganic layer was dried over MgSO₄, and concentrated in vacuo.Purification by flash chromatography on silica gel afforded 0.25 g (82%yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,as a yellow solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s,1), 9.5 (s,1), 9.2 (s, 1), 7.4-8.4 (m, 6), 4.8 (t, 2), 4.6 (s, 2), 3.7 (t, 2), 3.6(s, 4), 2.9 (s, 4) ppm.

B. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.30 g, 0.59 mmol) in DMF (5 mL) was added2-hydroxy-3-methoxypropylamine (1.0 g, 9.5 mmol) and the mixture wasstirred at ambient temperature. After 16 hours, the mixture wasacidified with trifluoroacetic acid and purified by HPLC on a C18Dynamax column with 20-60% acetonitrile in water gradient with 0.1%trifluoroacetic acid. To a solution of the resulting material inmethanol (5 mL) were added cyanogen bromide (5 M in acetonitrile, 0.1mL, 0.5 mmol) and K₂ CO₃ (0.3 g, 2.2) and the reaction was stirred atambient temperature. After 3 hours, the mixture was partitioned betweenethyl acetate and water, and the organic layer concentrated in vacuo.Purification by HPLC on a C18 Dynamax column with 20-60% acetonitrile inwater gradient with 0.1 % trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5-(methoxymethyl)oxazolidin-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt as a white solid: NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.6 (s, 1), 9.4 (s, 1), 9.2 (s, 1), 7.2-8.3 (m, 6), 5.2 (s, 1), 4.6(m, 2), 3.84.0 (m, 2), 3.9 (s, 3), 3.5-3.7 (m, 2), 3.3 (s, 3) ppm.

C. In a manner similar to that described in Paragraph A above, to asolution ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-aminoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.57 g, 1.08 mmol) in methanol (20 mL) - were added sodium acetate(0.18 g, 2.16 mmol) and cyanogen bromide (0.26 mL of 5 M -solution inacetonitrile, 1.29 mmol). After stirring for 3 hours at ambienttemperature, the reaction mixture was concentrated and saturated NaHCO₃(aq) was added. The reaction mixture was extracted with methylenechloride, and the combined extracts were dried over Na₂ SO₄. Theresulting product was filtered, concentrated, and purified by HPLC on aC18 Dynamax column with 20-95% acetonitrile in water gradient with 0.1 %trifluoroacetic acid to afford 0.37 g ofN-(5-chloropyridin-2-yl)-2-[((4-((2-imino-tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.4 (s, 1), 8.3 (s, 1), 8.1 (d, 2), 8.0 (br s, 1), 7.8 (dd, 1), 7.75(s, 1), 7.3 (d, 2), 4.5 (s, 2), 3.8 (s, 3), 3.5 (s, 4) ppm.

D. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((trans4,5-dimethyl-2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 9.1 (s, 1), 8.3 (d, 1),8.0 (d, 1), 7.6 (dd, 1), 7.5 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 7.2 (d, 1),7.1 (d, 1), 3.9 (m, 5), 3.6 (d, 1), 3.3 (m, 1), 2.5 (m, 1), 1.2 (d, 3),1.1 (d, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((cis4,5-dimethyl-2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 9.1 (d, 2), 8.3 (d, 1),8.0 (d, 1), 7.6 (dd, 1), 7.5 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 7.2 (d, 1),7.1 (d, 1), 3.9 (m, 6), 3.3 (m, 1), 2.7 (m, 1), 1.2 (d, 3), 1.1 (d, 3)ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-oxoimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.3 (s., 1),8.3 (d, 1), 8.1 (m, 2), 7.7 (d, 1), 7.6 (d, 1), 7.5 (s, 1), 7.3 (d, 1),7.2 (d, 1), 4.4 (s, 2), 4.3 (s, 2), 3.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-(hydroxymethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), ), 9.5 (br s,1), 9.4 (s, 1), 9.2 (br s, 1), 8.3 (s, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8(dd, 1), 7.3 (d, 2), 4.8 (m, 2), 4.5 (m, 2), 4.1 (m, 2), 3.8 (s, 3), 3.7(d, 1), 3.4 (d, 2) ppm; and

N-(5-chloropyridin-2-yl)-2-[((4-((tetrahydro-2-imino-2H-pyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.85 (s, 1), 9.30 (s, 1),8.30 (d, 1), 8.10 (d, 1), 7.80 (m, 2), 7.65 (s, 1), 7.20-7.30 (m, 4),4.45 (s. 2), 3.80 (s, 3), 3.20-3.30 (m, 4), 1.90 (m, 2) ppm.

E. To a mixture ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.0 mmol) and K₂ CO₃ (0.97 g, 7.0 mmol) in acetonitrile (20 mL)was added cyanogen bromide (0.8 mL of a 5 M solution in acetonitrile,4.0 mmol). After stirring at ambient temperature for 3 hours, thereaction was poured into water and extracted with ethyl acetate. Theethyl acetate extract was concentrated in vacuo and was purified byflash chromatography on silica gel to give 1.2 g ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-cyanoamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ / TFA) 10.9 (s, 1), 9.4 (s, 1), 8.3 (d, 1), 8.1 (m, 2), 7.8(dd, 1), 7.7 (s, 1), 7.4 (d, 1), 7.3 (d, 1), 4.3 (s, 2), 3.9 (s, 3), 2.9(s, 3) ppm.

F. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 19

A. To a suspension ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.10 g, 0.20 mmol) in ethanol (5 mL) was added chloroacetaldehydediethylacetal (0.3 mL, 2.0 mmol). The mixture was heated at reflux for 4days, then cooled to ambient temperature and poured onto water. Themixture was neutralized by addition of saturated NaHCO₃ solution and thesolid collected by filtration. Purification by HPLC on a C18 Dynamaxcolumn with 20-80% acetonitrile in water gradient with 0.1%trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(oxazol-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt as a white solid: NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.4 (s, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s, 1), 7.6 (s,1), 7.4 (d, 1), 7.3 (d, 1), 7.0 (s, 1), 4.5 (s, 2), 3.8 (s, 3), 3.0 (s,3) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 20

A. To a solution ofN-(4-chlorophenyl)-2-[((3-chloro4-((((2-hydroxyethoxy)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.25 g, 0.46 mmol) in acetonitrile (5 mL) was added formaldehyde (0.19mL of a 37% solution in water, 2.3 mmol), followed by NaCNBH₃ (0.045 g,0.69 mmol) and the mixture stirred at ambient temperature. After 2hours, the mixture was concentrated of all volatiles in vacuo.Purification by HPLC on a C18 Dynamax column with acetonitrile in watergradient with 0.1% trifluoroacetic acid affordedN-(4-chlorophenyl)-2-[((3-chloro-4-((N'-methyl-N'-(2-(hydroxyethoxy)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 11.2 (s,1), 10.8 (s, 1), 9.6 (br s, 1), 8.4 (d, 1), 8.3 (s, 1), 7.9 (s, 1), 7.7(d, 2), 7.6 (d, 1), 7.4 (d, 2), 4.5 (d, 1), 4.3 (d, 1), 3.8 (m, 2), 3.5(m, 4), 3.4 (br s, 1), 2.8 (s, 3) ppm.

B. In a similar manner, the following compounds were made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(hydroxyethoxy)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (br s,1), 9.5 (s, 1), 8.4 (s, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (d, 1), 7.4 (s,1), 7.3 (s, 1), 4.5 (d, 1), 4.3 (d, 1), 3.9 (s, 3), 3.8 (m, 2), 3.5 (m,4), 3.4 (br s, 2), 2.8 (s, 3) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-hydroxycyclohexyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (CDCl₃) 9.1 (s, 1), 9.0 (s, 1), 7.0-8.2 (m, 6), 4.4 (s, 2), 3.9 (s,3), 3.6 (m, 1), 3.5 (s, 2), 2.5 (m, 1), 2.2 (s, 3), 1.8-2.1 (m, 4), 1.4(m, 4) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-N'-((imidazol-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.90 (S, 1H), 9.30 (s, 1H),8.35 (d,₁ H), 8.10 (d, 1H), 7.90 (dd, 1H), 7.85 (s, 2H), 7.60 (s, 2H),7.40 (d,1H), 7.25 (d, ₁ H), 4.05 (s, 2H), 3.90 (s, 3H), 3.60 (s, 2H),2.50 (q, 2H), 1.00 (t, 3H) ppm; and

N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl-

N-(4-(dimethylamino)but-3-yn-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆) 10.90-10.85 (m, 1H), 9.40-9.30(m, 1HO, 8.38 (d, 1H), 8.10 (d, 1H), 7.90 (dd,1H), 7.65 (s,1H), 7.60(s,1H), 7.39 (d, 1H), 7.25 (d,1H), 4.42-3.38 (m, 2H), 3.90 (s, 3H),3.40-3.25 (m, 2H), 2.50 (s, 3H), 2.10-2.00 (m, 3H), 1.10-0.90 (m, 3H)ppm.

C.N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide,trifluoroacetic acid salt, (˜2 g, 2.7 mmol) was dissolved inacetonitrile (40 mL), and acetaldehyde (˜1 mL, 18 mmol) was added,followed by a few drops of acetic acid. After one hour, a few more dropsof acetic acid were added. After several hours, more acetaldehyde andacetic acid were added and the reaction mixture allowed to stir for 16hours at ambient temperature. More acetic acid (10 mL) was added and thereaction mixture stirred for one hour, then sodium cyanoborohydride(0.51 g, 8.0 mmol) was added to the reaction mixture. The reactionmixture was stirred for one hour, concentrated in vacuo, and the residuetaken up in ethyl acetate (100 mL). The ethyl acetate layer was washedwith 1 M sodium bicarbonate (2×5 mL), brine (50 mL), dried over MgSO₄,and concentrated in vacuo. The crude product was purified by reversephase preparatory HPLC and lyophilized to give 0.69 g (28% yield) of thetrifluoroacetic acid salt (monohydrate) of the compound,N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-ethylpiperazin-1-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.5 (s, 1), 7.4 (d, 2), 6.4 (br,1), 4.3 (s, 2), 3.6 (d, 2), 3.4 (d, 2), 3.2 (d, 3), 3.0 (d, 5), 2.8 (s,3), 1.2 (t, 3), 1.0 (t, 3) ppm.

D. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 21

A. To a solution ofN-(4-chlorophenyl)-2-[((3-chloro-5-((4-(ethoxycarbonylmethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.61 g, 1.0 mmol) in 3:1:1 (volume ratio)tetrahydrofuran/methanol/water (35 mL) was added lithium hydroxidemonohydrate (0.12 g, 3.0 mmol). The solution was stirred at ambienttemperature for 1 hour, then diluted with water (25 mL), adjusted to pH3 by addition of 1 N HCl and concentrated in vacuo to remove thetetrahydrofuran and methanol. The residual oil was diluted withacetonitrile, water and trifluoroacetic acid and purified by HPLC on aC18 Dynamax column with 50-65% acetonitrile in water gradient with 0.1 %trifluoroacetic acid to affordN-(4-chlorophenyl)-2-[((3-chloro-5-((4-(carboxymethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,trifluoroacetic acid salt as a white solid: NMR (DMSO-d₆ /TFA) 11.2 (s,1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.3-7.7 (m, 6), 4.4 (s, 2) 4.2(s, 2), 3.4 (br s, 4), 3.2 (br s, 4) ppm.

B. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-[((3-chloro-6-(4-(carboxymethyl)piperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide; (DMSO-d₆ /TFA)11.4 (s, 1), 10.8 (s, 1), 8.4 (d, 1), 8.3 (br s, 1), 8.1 (d, 1), 8.0 (d,1), 7.4-7.7 (m, 6), 4.6 (s, 2), 4.2 (s, 2), 3.5 (br s, 8) ppm;

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-carboxy)piperidin-1-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (s, 1),7.3-8.5 (m, 6), 4.2-4.5 (m, 2), 3.7 (t, 2), 3.6 (s, 3), 3.0-3.3 (m, 4),2.6-2.9 (m, 4), 1.6-2.0 (m, 4) ppm;

N-(5-chlorpyridin-2-yl)-2-[((4-((N'-methyl-N'-(4-trifluoromethyl-5-carboxypyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA)

10.9 (s, 1), 9.5 (s, 1), 8.9 (m, 1), 8.3 (br s, 1), 8.1 (m, 1), 7.8 (m,1), 7.6 (m, 1), 7.6 (m, 1), 7.4 (s, 2), 4.8 (s, 2), 3.6 (m, 4), 3.2 (s,3), 2.9 (m, 4) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-5-carboxythiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

N-(4-chlorophenyl)-2-[((3-chloro-5-(N'-methyl-N'-(carboxymethyl)amino)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;and

N-(4-chlorophenyl)-2-[((3-chloro-5-(((carboxymethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.

C. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 22

A. To a suspension ofN-(4-chlorophenyl)-2-[((3-chloro-5-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.1 g, 0.2 mmol) in methanol (20 mL) at 0° C. was added a solution ofpotassium peroxymonosulfate (0.13 g, 0.2 mmol) in water (5 mL). After 5minutes, the reaction was quenched by addition of aqueous 5% sodiumbisulfite solution. The mixture was extracted with methylenechloride/methanol, and the organic phase dried over Na₂ SO₄ andconcentrated in vacuo. Purification by flash chromatography on silicagel afforded 0.064 g (62% yield) of

N-(4-chlorophenyl)-2-[((3-chloro-5-(1-(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,as a pale yellow powder; NMR (DMSO-d₆ /TFA) 11.2 (s, 1), 10.7 (s, 1),8.3 (d, 1), 7.9 (s, 1), 7.7 (m, 2), 7.6 (m, 1), 7.4 (m, 3), 4.7 (s, 2),3.7 (m, 2), 3.5 (m. 2), 2.9 (br s, 4) ppm.

B. In a similar manner, the following compounds were made:

N-(4-chlorophenyl)-2-[((3-chloro-5-((methylsulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (dd, 1), 7.9 (d, 1), 7.8(dd, 2), 7.7 (dd, 1), 7.4 (d, 2), 7.2 (s, 1), 4.4 (dd, 2), 3.3 (s, 3)ppm;

N-(4-chlorophenyl)-2-[((3-chloro-5-((methylsulfonyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (br d, 1), 7.9 (s, 1),7.8-7.6 (br m, 3), 7.4 (br d, 2), 7.2 (s, 1), 4.8 (s, 2), 3.0 (s, 3)ppm;

N-(4-chlorophenyl)-2-[((3-chloro-5-(((2-(dimethylamino)ethyl)sulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.7 (d,2), 7.5 (d, 1), 7.3 (d, 2), 7.2 (s, 1), 4.4 (dd, 2), 3.4 (m, 2), 3.2-2.8(m, 2), 2.7 (s, 6) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((methylsulfonyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 8.1 (s, 1), 7.9 (s,1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 4.6 (s, 2), 3.0 (s, 3) ppm;

N-(4-chlorophenyl)-2-[((3-chloro-4-((methylsulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.1 (s, 1), 10.7 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.8 (s,1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 4.1 (dd, 2), 2.5 (s, 3) ppm;and

N-(4-chlorophenyl)-2-[((3-chloro-5-(1,1,4-tri(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.

C. To a solution of

N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(2.0 g, 4.0 mmol) in DMF (40 mL) was added sodium thiomethoxide (1.4 g,20 mmol). The mixture was stirred at ambient temperature for 16 hours,then poured onto ice water (200 mL), filtered, and dried to give 1.55 gcrude product,N-(5-chloropyridin-2-yl)-2-[((4-((methylthio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.To a solution of the product in CH₂ Cl₂ (30 mL) at -20° C. was added3-chloroperoxybenozic acid (mCPBA) (0.71 g, 3.3 mmol) in two equalportions. After 2 hours, the reaction was poured onto ice water (200mL). The resulting solid was collected by filtration and washed with CH₂Cl₂ (30 mL) and THF (5 mL) to afford 0.72 g (34% yield) ofN-(5-chloropyridin-2-yl)-2-[((4-((methylsulfinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a tan solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.3 (s, 1),8.1 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.4 (s,1), 7.3 (s, 1), 4.2 (d, 1),4.0 (d, 1), 3.9 (s, 3), 2.6 (s, 3) ppm.

D. In a similar manner, the following compound was made:

N-(4-chlorophenyl)-2-[((3-chloro-5-(((methoxycarbonylmethyl)sulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.

E. In a manner similar to that described in Paragraph C above,N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.20 g, 0.42 mmol) reacted with morpholine (0.18 mL, 2.1 mmol),followed by mCPBA (0.24 g, 0.84 mmol) to affordN-(4-chlorophenyl)-2-[((3-chloro4-((4-oxomorpholin-4-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.Purification by HPLC on a C18 Dynamax column with 20-80% acetonitrile inwater gradient with 0.1% trifluoroacetic acid afforded thetrifluoroacetic acid salt as a white solid; NMR (DMSO-d₆ /TFA) 11.2 (s,1), 10.8 (s, 1), 8.4 (d, 1), 8.3 (s, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (d,1), 7.4 (d, 2), 4.9 (s, 2), 3.9 (m, 6), 3.5 (m, 2) ppm.

F. In a similar manner, the following compound was made:

N-(5-chloropyridin-2-yl)-2-[((4-(((2-hydroxyethyl)sulfinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.8 (s, 1), 9.4 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.8(m, 1), 7.3 (s, 1), 7.2 (s, 1), 4.2 (d, 1), 4.0 (d, 1), 3.9 (s, 3), 3.8(m, 2), 2.9 (m, 1), 2.8 (m, 1) ppm.

G. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 23

A. A solution of

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide(4.7 g, 6.5 mmol) in methylene chloride (30 mL) and trifluoroacetic acid(3 mL) was stirred at ambient temperature. After one hour, additionaltrifluoroacetic acid (10 mL) was added and the reaction stirred for anadditional 3 hours. The mixture was then concentrated and dried in vacuotoN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(piperazin-1-yl)-5-chlorobenzamide,trifluoroacetic acid salt as a light brown oil; NMR (DMSO-d₆): 10.9 (s,1), 9.4 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.5 (s, 1), 7.4 (s,2), 4.3 (s, 2), 3.1 (m, 10), 2.8 (s, 3), 1.0 (t, 3) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 24

A.N-(4-chlorophenyl)-2-[((3-chloro-4-(((2,2-dimethyldioxolan-4-yl)methoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide9955 (0.10 g, 0.17 mmol) was stirred in a mixture of 1 M HCl (1.0 mL)and THF (1.0 mL) at ambient temperature. After 16 hours, the mixture waspoured onto water and extracted with ethyl acetate. The organic layerwas dried over Na₂ SO₄ and concentrated in vacuo. Purification by HPLCon a C18 Dynamax column with acetonitrile in water gradient with 0.1%trifluoroacetic acid afforded

N-(4-chlorophenyl)-2-[((3-(2,3-dihydroxypropoxy)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.0 (s, 1), 10.7 (s, 1), 8.3 (d, 1), 7.9 (d, 2), 7.7 (d,2), 7.6 (d, 1), 7.4 (d, 2), 4.4 (s, 2), 3.5 (m, 1), 3.4 (m, 1), 3.3 (m,2) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 25

A. A solution ofN-(5-chloropyridin-2-yl)-2-[((4-cyano-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.10 g, 0.21 mmol) in absolute ethanol (15 mL) was cooled to -78° C.and HCl(g) was bubbled through the mixture for 15 minutes. The resultantmixture was stirred at ambient temperature in a sealed vessel for 20hours, then concentrated of all volatiles in vacuo without heating. Theresidue was dissolved in absolute ethanol (10 mL) and treated with1,2-diaminoethane (0.14 mL, 2.1 mmol) at 60° C. After 1 hour the mixturewas cooled to ambient temperature and concentrated in vacuo.Purification by chromatography on silica gel, followed by lyophilizationfrom aqueous trifluoroacetic acid affordedN-(5-chloropyridin-2-yl)-2-[((4-(imidazolin-2-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt as a yellow solid; NMR (CDCl₃) 10.9 (s, 1),10.4 (s, 1), 9.7 (s, 1), 8.6 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9 (d, 1),7.3 (d, 2), 4.0 (s, 4), 3.9 (s, 3) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 26

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.093 g, 0.19 mmol) in methylene chloride (4.0 mL) was added mCPBA(0.044 g, 0.20 mmol) The reaction mixture was stirred at ambienttemperature for 16 hours. The mixture was poured into ethyl acetate (20mL) and washed with saturated aqueous sodium bicarbonate (2×5 mL). Theorganic layer was dried and concentrated in vacuo to give the crudepyridine N-oxide. The crude material was dissolved in DMF (3.0 mL) andtrimethylethylene diamine (0.115 mL, 0.9 mmol) was added. The reactionwas stirred for 16 hours at ambient temperature and poured into waterand ethyl acetate. The ethyl acetate layer was washed with water (2×2mL) and concentrated. Purification by HPLC on a C18 Dynamax column withacetonitrile in water gradient with 0.1 % trifluoroacetica acid afforded0.028 g ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamideN-oxide, trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.6 (br s, 1),9.8 (s, 1), 8.6 (d, 1), 8.3 (d, 1), 8.2 (s, 1), 7.6 (dd, 1), 7.4 (dd,2), 4.4 (s, 2), 3.9 (s, 3), 3.6 (s, 4), 2.9 (s, 6), 2.8 (s, 3) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 27

A. Hydroxylamine hydrochloride (0.58 g, 8.3 mmol) was dissolved in asolution of sodium methoxide prepared by dissolving sodium (0.17 g) inmethanol (50 mL).N-(5-chloropyridin-2-yl)-2-[((4-cyanomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(2.56 g, 5.2 mmol) and additional methanol (30 mL) were then added. Thereaction mixture was refluxed for 16 hours, then a solution ofhydroxylamine hydrochloride (0.67 g, 9.6 mmol) in sodium methoxide (0.20g sodium, 25 mL methanol) was added. The reaction mixture was refluxedfor 24 hours, then a solution of hydroxylamine hydrochloride (0.63 g,9.1 mmol) in sodium methoxide (0.19 g sodium, 60 mL methanol) was added.The reaction mixture was refluxed for an additional 24 hours, filteredhot, concentrated in vacuo, and dried under vacuum. Purification by HPLCon a C18 Dynamax column with 20-70% acetonitrile in water gradient with0.1 % trifluoroacetic acid gave

N-(5-chloropyridin-2-yl)-2-[((4-(2-amino-2-(hydroxylmino)ethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a white solid; NMR (DMSO-d₆) 10.9 (s, 1),9.4 (d, 1), 8.9 (br, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (s,0.5), 7.7 (s, 0.5), 7.4 (d, 1), 7.2 (d, 1), 3.9 (s, 3), 3.7 (s, 2) ppm.

B. In a similar manner, the following compound was made:

N-(5-chloropyridin-2-yl)-2-[((4-(N'-methyl-N'-hydroxyguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 10.6 (s, 1),9.4 (s., 1 ), 8.4 (d, 1), 8.1 (m, 2), 7.9 (dd, 1), 7.7 (s, 1), 7.4 (d,1), 7.3 (d, 1), 4.5 (s, 2), 3.9 (s, 3), 3.0 (s, 3) ppm.

C. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 28

A. ToN-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.5 g, 3.0 mmol) in DMF (15 mL), was added ethylene diamine (0.09 g, 15mmol) at ambient temperature. After 2 hours, the reaction was pouredinto water and extracted with ethyl acetate. The ethyl acetate solutionwas dried (NaSO₄) and concentrated in vacuo to afford the crude amineadduct. To the adduct was added triethyl orthoformate (1.33 g, 9 mmol)in acetic acid (20 mL). After stirring at ambient temperature for 1hour, the reaction was poured into water and extracted with ethylacetate. The ethyl acetate layer was dried (NaSO₄), concentrated invacuo, and purified by HPLC on a C18 Dynamax column with acetonitrile inwater gradient with 0.1 % trifluoroacetic acid to afford 0.87 g ofN-(5-chloropyridin-2-yl)-2-[((4-((imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(870 mg), trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1),10.3 (s., 1 ), 9.4 (s, 1), 8.6 (d, 2), 8.3 (d, 1), 8.1 (d, 1), 7.8 (dd,1), 7.3 (d, 1), 7.2 (d, 1), 4.6 (s, 2), 3.7˜3.9 (m, 7) ppm.

B. In a similar manner, the following compound was made:

N-(5-chloropyridin-2-yl)-2-[((4-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.9 (s., 1),9.4 (s, 1), 8.5 (d, 1), 8.4 (d, 1), 8.1 (d, 1), 8.0 (s, 1), 7.8 (dd, 1),7.3 (d, 1), 7.2 (d, 1), 4.6 (m, 2), 4.62 (brs, 1), 3.9 (s, 3), 3.1˜3.6(m, 4) ppm.

C. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 29

A. To a mixture of

N-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.053 g, 0.96 mmol) and sulfuric acid (0.10 g, 1.06 mmol) in methanol(10 mL) was added N-chlorosuccinimide (0.192 g, 1.43 mmol). Afterstirring at ambient temperature for 6 hours, the reaction was pouredinto water and extracted with ethyl acetate. The ethyl acetate extractwas dried over sodium sulfate, concentrated in vacuo, and purified byflash chromatography on silica gel to give 0.33 g ofN-(5-chloropyridin-2-yl)-2-[((4-((cis4,5-dimethoxy-2-iminotetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (CDCl₃) 9.0 (d, 2), 8.3 (d, 1), 8.1 (d, 1), 7.7 (dd, 1), 7.5 (s, 1),7.3 (d, 1), 7.1 (d, 1), 6.0 (brs, 1), 4.8 (m, 2), 4.6 (d, 1), 4.3 (d,1), 3.9 (s, 3), 3.4 (s, 3), 3.3 (s, 3) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 30

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-aminoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.64 g, 1.2 mmol) and triethylamine (0.31 g, 3.1 mmol) indichloromethane (20 mL) at 0° C. was added POCl₃ (0.14 g, 0.923 mmol).The reaction was allowed to warm to ambient temperature and stirred for16 hours. The reaction was quenched with methanol, concentrated invacuo, and purified by HPLC on a C18 Dynamax column with acetonitrile inwater gradient with 0.1% trifluoroacetic acid to afford 0.13 g ofN-(5-chloropyridin-2-yl)-2-[((4-(((2-dimethylphosphoramidoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.9 (br s, 1), 8.4 (d, 1), 8.2 (d, 1), 8.1 (s, 1), 7.9 (dd, 1), 7.4 (s,1), 7.3 (s, 1), 4.2 (s, 2), 3.9 (s, 3), 3.6 (s, 3), 3.55 (s, 3), 3.1 (m,4) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 31

A. To a mixture ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.70 g, 1.4 mmol) and triethylamine (0.16 g, 1.5 mmol) indichloromethane (7 mL) was added ethylene chlorophosphate (0.19 g, 1.5mmol) at 0° C. The reaction was allowed to warm to ambient temperatureand stirred for 2 hours. The reaction was then quenched with methanol.The reaction mixture was poured into water and extracted with ethylacetate. The ethyl acetate extract was concentrated in vacuo andpurified by flash chromatography on silica gel to give 0.70 g ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(1,3,2-dioxaphospholan-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (d, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9(dd, 1), 7.7 (s, 1), 7.4 (d, 1), 7.3 (d, 1), 4.4 (m, 4), 4.2 (d, 2), 3.9(s, 3), 2.6 (d, 3) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 32

A. A mixture ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-aminoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.5 g, 2.9 mmol) and triethyl orthochloroacetate (1.3 g, 8.6 mmol) inacetic acid (10 mL) was stirred at ambient temperature for 16 hours. Thesolvent was removed in vacuo and the resulting residue was purified byHPLC on a C18 Dynamax column with acetonitrile in water gradient with0.1% trifluoroacetic acid to afford 0.14 g of

N-(5-chloropyridin-2-yl)-2-[((4-((2-(chloromethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt. The product (0.14 g, 0.24 mmol) was treatedwith tetrabutylammonium cyanide (0.097 g, 0.36 mmol) in acetonitrile (3mL) and the mixture stirred at ambient temperature for 16 hours. It wasthen purified directly by HPLC on a C18 Dynamax column with acetonitrilein water gradient-with 0.1 % trifluoroacetic acid to afford 0.020 g ofN-(5-chloropyridin-2-yl)-2-[((4-((2-(cyanomethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.8 (br s,1), 9.4 (d, 1), 8.4 (d, 1), 8.2 (d, 1), 8.1 (s, 1), 7.9 (dd, 1), 7.4 (d,1), 7.3 (d, 1), 4.7 (s, 2), 4.5 (brs, 2), 3.7-3.9 (m, 7) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 33

A. A mixture ofN-(5-chloropyridin-2-yl)-2-[((4-((2-(methylthio)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.60 g, 1.03 mmol) and 2-aminoethanol (0.18 g, 3.1 mmol) was refluxedin isopropanol for 16 hours. After removal of the solvent in vacuo, theresulting crude product was purified by HPLC on a C18 Dynamax columnwith acetonitrile in water gradient with 0.1% trifluoroacetic acid toafford 0.13 g ofN-(5-chloropyridin-2-y)-2-[((4-((2-((2-hydroxyethyl)imino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (d, 1),8.4 (brs, 2), 8.3 (d, 1), 8.1 (d, 1), 7.7 (m, 1), 7.6 (s, 1), 7.3 (d,1), 7.2 (d, 1), 4.5 (s, 2), 3.9 (s, 3), 3.4 3. 7 (m, 6), 3.2-3.35 (m, 2)ppm.

B. A mixture of

N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylthio)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.88 g, 1.5 mmol), glycinamide hydrochloride (0.33 g, 3.0 mmol) anddiisopropylethylamine (0.49 g, 3.8 mmol) in DMF was stirred at 75-80° C.for 10 hours. The reaction was then poured into water and extracted withethyl acetate. The ethyl acetate layer was dried over sodium sulfate,concentrated in vacuo, and purified by HPLC on a C18 Dynamax column withacetonitrile in water gradient with 0.1 % trifluoroacetic acid to afford0.47 g of

N-(5-chloropyridin-2-yl)-2-[((4-((2-(((aminocarbonyl)methyl)imino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 9.4 (d, 1), 8.6 (br s, 2),8.2 (d, 1), 8.1 (d, 1), 7.6 (m, 2), 7.4 (br s, 1), 7.2 (br s, 1), 4.5(s, 2), 3.9 (s, 5), 3.6 (m, 4) ppm.

C. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 34

A. A mixture ofN-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.0 mmol) and 2-formylimidazole (1.2 g, 12.5 mmol) in DMF wasstirred at 110° C. for 10 hours. After cooling to ambient temperature,the reaction mixture was poured into water and extracted with ethylacetate. The ethyl acetate extract was concentrated in vacuo andpurified by flash chromatography on silica gel to give the imidazoleadduct. To the imidazole adduct in methanol (10 mL) at 0° C. was addedNaBH₄ until thin layer chromatography indicated the completion of thereaction. The reaction was poured into water and extracted with ethylacetate. The ethyl acetate extract concentrated in vacuo and purified byHPLC on a C18 Dynamax column with acetonitrile in water gradient with0.1% trifluoroacetic acid to afford to give 0.21 g of

N-(5-chloropyridin-2-yl)-2-[((4-((2-(hydroxymethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ / TFA) 10.9 (s,1), 9.4 (d, 1),8.3 (d, 1), 8.1 (d, 1), 7.9 (m, 2), 7.6 (s, 2), 7.35 (d, 1), 7.25 (d,1), 5.4 (s, 2), 4.8 (s, 2), 3.9 (s, 3) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 35

A.N-(5-Chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-nitro-1-methylthioethenyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.185 g, 0.30 mmol) was dissolved in DMF (3 mL) under nitrogen. A 2.0 Msolution of methylamine in THF (0.75 mL, 1.5 mmol) was added. Thereaction mixture was stirred at ambient temperature for 16 hours, thenpoured into water (50 mL). The aqueous layer was extracted with ethylacetate (3×30 mL). The combined organic layers were washed with water(3×40 mL), brine (40 mL), dried over magnesium sulfate, concentrated invacuo, and dried under vacuum. Purification by HPLC on a C18 Dynamaxcolumn with acetonitrile in water gradient with 0.1 % trifluoroaceticacid affordedN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-nitro-1-(methylamino)ethenyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a mixture of geometric isomers; NMR(DMSO-d₆) 10.9 (d, 1), 9.6 (br, 0.5), 9.4 (s, 1), 8.8 (br, .5), 8.4 (d,1), 8.1 (d, 1), 7.9 (dd, 1), 7.85 (s, 0.33), 7.75 (s, 0.33), 7.7 (s,0.33), 7.4 (d, 1), 7.2 (d, 1), 6.2 (s, 1), 4.9 (s, .67), 4.7 (s, 0.67),4.4 (s, 0.67), 3.9 (s, 3), 3.3 (s, 1), 3.2 (s, 1), 3.1 (d, 1), 3.0 (d,1), 2.9 (d, 1), 2.8 (s, 1) ppm.

B. In a similar manner the following compound was made:

N-(5-chloropyridin-2-yl)-2-[((4-(N'-methyl-N"-(2-aminoethyl)-N'"-cyanoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1),8.3 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.8 (br s, 2), 7.7 (s, 1), 7.3 (d,2), 7.2 (s, 1), 4.6 (s, 2), 3.8 (s, 3), 3.5 (m, 2), 2.9 (br s, 5) ppm.

C. To a solution of

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylthio(cyanoimino)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.1 g, 0.17 mmol) in DMF (10 mL) was added methylamine (0.84 mL of a 2M solution in THF, 1.7 mmol). After stirring for 16 hours at ambienttemperature, the reaction mixture was concentrated in vacuo to removeTHF, poured into water and filtered. The resulting solid was purified bysilica gel chromatography using 1-8% methanol in methylene chloridegradient followed by precipitation from CH₂ CI₂ and hexane to afford0.072 g ofN-(5-chloropyridin-2-yl)-2-[((4-(N',N"-dimethyl-N'"-cyanoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s,1), 8.3 (s, 1),8.1 (d, 1), 7.9 (dd, 1), 7.6 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 7.2 (br d,1), 4.5 (s, 2), 3.8 (s, 3), 2.9 (d, 3), 2.85 (s, 3) ppm.

D. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 36

A. Dimethylamine (40% aqueous, 0.51 mL, 4.1 mmol) was dissolved in DMF(2 mL) under nitrogen, andN-(5-chloropyridin-2-yl)-2-[((4-((5-trichloromethyl-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.151 g, 0.23 mmol) was added. The reaction mixture was stirred for 40minutes at ambient temperature, then poured into water (40 mL). Theaqueous layer was extracted with ethyl acetate (3×25 mL). The combinedorganic layers were washed with water (3×25 mL), brine (25 mL), driedover magnesium sulfate, concentrated in vacuo, and dried under vacuum.The crude product was purified by flash chromatography on silica gel,eluting with 75% ethyl acetate/hexanes to affordN-(5-chloropyridin-2-yl)-2-[((4-((5-(dimethylamino)-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (br, 1), 9.4 (br, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9(dd, 1), 7.8 (s, 1), 7.4 (d, 1), 7.2 (d, 1), 3.9 (s, 3), 3.8 (s, 2), 3.0(s, 6) ppm.

B. In a similar manner, the following compound was prepared,

N-(5-chloropyridin-2-yl)-2-[((4-((5-amino-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 1), 9.4 (s, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd,1), 7.7 (s, 3), 7.4 (d, 1), 7.2 (d, 1), 3.9 (s, 3), 3.8 (s, 2) ppm.

C. Other compounds of the invention may be prepared by methods similarto those 10 described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 37

A.N-(4-chlorophenyl)-2-[(((4,5)-nitro-3-methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(1 g, 2.1 mmol) was stirred in a 4:1 ethanol/water solution (43 mL). Tothis 15 solution was added iron (0.59 g, 10.6 mmol), and ammoniumchloride (5.0 eq.) and the reaction mixture was refluxed for 1 hour. Thereaction mixture was cooled to ambient temperature, filtered throughCelite®, and the Celite® layer was washed with methylene chloride andethyl acetate. The filtrate was washed with aqueous sodium bicarbonate,water and dried over sodium sulfate to afford a rust-colored solid, 0.71g (75% yield). Purification by flash chromatography on silica, elutingwith 1:1 ethyl acetate/hexanes afforded

N-(4-chlorophenyl)-2-[((5-amino-3-methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.7 (s, 1), 10.6 (s, 1), 8.4 (d, 1), 8.0 (s, 1), 7.8(d, 2), 7.6 (d, 1), 7.4 (d, 2), 5.8 (s, 1) 2.4 (s, 3) ppm, andN-(4-chlorophenyl)-2-[((4-amino-3-methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.

B. To a solution ofN-(4-chlorophenyl)-2-[((5-amino-3-methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.05 g, 0.114 mmol) in pyridine (3 mL) at 0° C. was added acetylchloride (0.009 mL, 0.125 mmol) and the reaction was warmed to ambienttemperature. The reaction was stirred 3 hours and was poured into waterand ice. The resulting solid was collected by filtration, washed withwater and dried in vacuo to afford 0.03 g 30 (55%) of

N-(4-chlorophenyl)-2-[((5-acetamido-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (DMSO-d₆) 11.4 (s, 1), 10.8 (s, 1), 10.7 (s, 1), 8.3 (d, 1), 7.9 (s,1), 7.8 (d, 2), 7.6 (d, 1), 7.4 (d, 2), 6.5 (s, 1), 2.4 (s, 3), 2.0 (d,3) ppm.

C. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 38

A. A suspension ofN-(5-chloropyridin-2-yl)-2-[((4-(N',N"-dimethyl-N'"-cyanoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.3 g, 0.52 mmol) in 3 M HCl (10 mL) was stirred for 24 hours atambient temperature. The reaction mixture was made pH basic with 2 NNaOH and saturated aqueous NaHCO₃. The reaction mixture was filtered,and the solid was dissolved in methylene chloride. The solution wasdried over Na₂ SO₄, filtered, concentrated, and purified by flashchromatography on silica using 1-8% methanol in methylene chloridegradient followed by precipitation from CH₂ Cl₂ and hexane to afford0.115 g ofN-(5-chloropyridin-2-yl)-2-[((4-(N'N"-dimethyl-N'"-(aminocarbonyl)guanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.4 (s, 1), 8.8 (br s,1), 8.3 (s, 1), 8.1 (d, 1), 7.8 (m, 2), 7.3 (d, 2), 6.9 (br m, 1), 4.6(s, 2), 3.8 (s, 3), 3.0 (s, 3), 2.9 (d, 3) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 39

A. To a solution of

N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-aminoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.9 g, 1.7 mmol) in DMF (50 mL) was added excess of dimethylN-cyanodithioimidocarbonate. After stirring for 16 hours at ambienttemperature, the reaction mixture was concentrated in vacuo. Water wasadded, and the reaction mixture was extracted with methylene chloride.The combined extracts were dried over Na₂ SO₄, filtered, concentrated,and purified by flash chromatography on silica using 1-8% methanol inmethylene chloride to afford a white solid. The solid was dissolved inacetonitrile and heated at reflux for for 16 hours. The solution wasconcentrated and purified by HPLC on a C18 Dynamax column with 25-95%acetonitrile in water gradient with 0.1% trifluoroacetic acid to afford0.084 g ofN-(5-chloropyridin-2-yl)-2-[((4-((2-(cyanoimino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt, as a white solid; NMR (DMSO-d₆ /TFA) 10.9 (s,1), 9.4 (s, 1), 8.4 (s, 1), 8.1 (d, 1), 8.0 (s, 1), 7.9 (dd, 1), 7.8 (s,1), 7.4 (s, 1), 7.3 (s, 1), 4.3 (s, 2), 3.8 (s, 3), 3.4 (m, 4) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 40

A. To a solution ofN-(4-chlorophenyl)-2-[((5-bromomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.3 g, 0.58 mmol) in dioxane (10 mL) and water (2 mL) was added CaCO₃(0.29 g, 2.89 mmol). The resulting turbid solution was heated to refluxfor 64 hours, and then cooled to ambient temperature. The reactionmixture was concentrated to remove dioxane and purified by flashchromatography on silica followed by precipitation from CH₂ Cl₂ andhexane to afford 0.15 g of

N-(4-chlorophenyl)-2-[((5-hydroxymethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,as a yellow solid; NMR (DMSO-d₆ /TFA) 11.1 (s, 1), 10.7 (s, 1), 8.4 (d,1), 7.9 (s, 1), 7.7 (d, 2), 7.5 (d, 1), 7.3 (d, 2), 7.0 (s, 1), 4.6 (s,2) ppm.

B. To a solution ofN-(4-chlorophenyl)-2-[((5-hydroxymethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.085 g, 0.19 mmol) in DMF (6 mL) was added pyridinium dichromate (PDC)(0.25 g, 0.65 mmol) at ambient temperature. After stirring for 20 hours,water was added and the reaction mixture was extracted with methylenechloride. The combined extracts were dried over Na₂ SO₄, filtered,concentrated in vacuo, and purified by flash chromatography on silica toafford 0.035 g ofN-(4-chlorophenyl)-2-[((5-formyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide,as a pale yellow solid; NMR (DMSO-d₆) 11.3 (s, 1), 10.8(s, 1), 9.9 (s,1),8.3 (d, 1), 8.1 (s, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (d, 1), 7.4 (d,2) ppm.

C. To a solution ofN-(4-chlorophenyl)-2-[((5-formyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide(0.31 g, 0.69 mmol) in CCl₄ (10 mL) and benzene (15 mL) was addedN-bromosuccinimide (NBS) (0.18 g, 1.03 mmol) and2,2'-azobisisobutyronitrile (AIBN) (0.011 g, 0.068 mmol). The reactionmixture was heated to reflux for 1 hour, and the resulting clear yellowsolution was cooled to 0° C. Methanol (0.1 mL) was added and thereaction mixture was stirred for 14 hours at ambient temperature. Waterwas added and the reaction mixture was extracted with methylenechloride. The combined extracts were dried over Na₂ SO₄, filtered,concentrated in vacuo, and purified by flash chromatography on silica toafford 0.27 g ofN-(4-chlorophenyl)-2-[((5-methoxycarbonyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.as a pale yellow solid; NMR (DMSO-d₆ /TFA) 11.3 (s,1), 10.8 (s, 1), 8.3(d, 1), 7.9 (s, 1), 7.7 (m, 3), 7.6 (d, 1), 7.4 (d, 2), 3.8 (s, 3) ppm.

D. In a similar manner, the following compound was made:

N-(4-chlorophenyl)-2-[((5-(diethylamino)carbonyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;NMR (CDCl₃) 11.0 (s, 1), 9.2 (s, 1), 8.4 (d, 1), 7.7 (d, 2), 7.5 (s,1),7.4 (d, 1), 7.3 (d, 1), 7.2 (d, 1), 7.0 (s, 1), 3.5 (q, 4), 1.2 (t, 6)ppm.

E. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 41

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(5.0 g, 8.03 mmol) in ethanol (50 mL) at 40° C. was added salicylic acid(1.22 g, 8.03 mmol) followed by the addition of ethyl acetate (125 mL).The solution was seeded with previously prepared crystals of thesalicylic acid salt ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.Crystallization occurred as the solution cooled to ambient temperature.After 1 hour at ambient temperature the crystalline product was isolatedby filtration. The solid was washed with ethyl acetate (50 mL), thendried in vacuo at 35° C. for 24 hours to afford 5.4 g (87%) of thesalicylic acid salt ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,as a white solid. A vial was charged with salicylic acid salt ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(200 mg). The vial was placed in an oil bath at 145° C. to melt thesolid then allowed to cool to ambient temperature to affordN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N"-(2-(((2-hydroxyphenyl)carbonyl)oxy)ethyl)ureido)-methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,in quantitative yield as an off-white solid; NMR (DMSO-d₆) 10.9 (s,0.5), 10.5 (s, 0.5), 9.3 (s, 0.5), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1),7.8 (dd, 1), 7.5 (m, 2), 7.4 (d, 1) 7.3 (d, 1), 6.9 (m, 2), 6.7 (t, 1),4.3 (m, 4), 3.9 (s, 3), 3.4 (d, 2), 3.3 (d, 4), 2.7 (s, 3) ppm.

B. In a similar manner, the following compound was made:

N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N!-(2-(acetoxy)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆) 10.9 (s, 0.5), 9.3 (s, 0.5), 8.4 (s, 1), 8.1 (d, 1), 7.9(dd, 1), 7.5 (s, 1), 7.4 (d, 1) 7.3 (d, 1), 6.6 (t, 1), 4.4 (s, 2), 4.0(t, 2), 3.9 (s, 3), 3.4 (d, 2), 3.3 (m, 2), 2.8 (s, 3), 2.0 (s, 3) ppm.

C. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 42

A. To a solution ofN-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.70 g, 1.4 mmol) in THF (10 mL) at 0° C. was added2-bromoethylisocyanate (0.63 mL, 4.2 mmol) and the mixture stirred atambient temperature. After 30 minutes, the mixture was cooled,concentrated in vacuo and the residue dissolved in DMF (4 mL).Pyrrolidine (0.50 g, 7.0 mmol) was added. The reaction was stirred for 1hour and poured into water and ethyl acetate. The ethyl acetate layerwas dried over MgSO₄ and concentrated in vacuo. Purification by flashchromatography on silica gel afforded 0.050 g ofN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.6 (m,1), 9.4 (s, 1), 8.3 (d, 1), 8.1(d, 1), 7.9 (dd, 1), 7.5 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 4.4 (s, 2), 3.9(s, 3), 3.6 (m, 2), 3.4 (m, 2), 3.2 (m, 2), 3.0 (m, 2), 2.9 (s, 3), 2(m, 2), 1.8 (m, 2) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 43

A. To a mixture ofN-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.072 g, 1.3 mmol) and triethyl amine (0.13 g, 1.3 mmol) indichloromethane (100 mL) was added methylchloroformate (0.12 g, 1.3mmol) at 0° C. The reaction was allowed to warm and stirred at ambienttemperature for 1 hour. The reaction was then quenched with methanol,and extracted between ethyl acetate and water. The ethyl acetate extractwas purified by HPLC on a C18 Dynamax column with acetonitrile in watergradient with 0.1% trifluoroacetic acid to afford 0.12 g ofN-(5-chloropyridin-2-yl)-2-[((4-((2-(methoxycarbonylamino)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.5 (s.,₁ ),9.4 (s, 1), 8.3 (d, 2), 8.1 (d, 1), 7.9 (m, 2), 7.4 (d, 1), 7.3 (d, 1),4.6 (s, 2), 3.9 (s, 3), 3.8 (s, 3), 3.6 (m, 4) ppm.

B. In a similar manner, to a mixture of

N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(0.56 g, 1.0 mmol) and triethyl amine (0.41 g, 3.0 mmol) indichloromethane (100 mL) was added phenylisocyanate (0.36 g, 3.0 mmol)at 0C. The reaction was allowed to warm and stirred at ambienttemperature for 1 hour. The reaction was then quenched with methanol,and extracted between ethyl acetate and water. The ethyl acetate extractwas purified by HPLC on a C18 Dynamax column with acetonitrile in watergradient with 0.1 % trifluoroacetic acid to afford 0.12 g ofN-(5-chloropyridin-2-yl)-2-[((4-((2-imino-3-((phenylamino)carbonyl)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,trifluoroacetic acid salt; NMR (DMSO-d₆ /TFA) 10.9 (s, 1), 9.7 (s.,1 ),9.6 (s, 1), 9.4 (s, 1), 8.3 (s, 1), 8.1 (d, 1), 7.9 (s, 1), 7.8 (dd, 1),7.1˜7.5 (m, 7), 4.6 (s, 2), 3.9 (s, 3), 3.6˜3.8 (m, 4) ppm.

C. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 44

A. 3-Methyl-2-formylbenzo[b]thiophene (0.68 g, 3.83 mmol) andN'-(4-chlorophenyl)-2-amino-5-benzamide (1.0 g, 3.83 mmol) were stirredat 0° C. in acetic acid (20 mL) for 2 hours. Sodium cyanoborohydride(0.48 g, 7.64 mmol) was added and the reaction stirred for 16 hours atambient temperature. The reaction was poured into water and theresulting pale yellow precipitate was collected by filtration.Purification by flash chromatography in ethyl acetate/hexanes afforded0.14 g (10%) ofN'-(4-chlorophenyl)-2-((3-methylbenzo[b]thien-2yl)methyl)amino-5-benzamideas a white solid; NMR (CDCl₃) 7.8 (s, 1), 7.7 (s, 1), 7.6 (s, 1), 7.5(d, 2), 7.4 (m, 3), 7.2 (d, 2), 6.8 (d, 2), 4.6 (s, 2), 2.4 (s, 3), 2.3(s, 3) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 45

A. To a solution ofN-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dihydroxybenzamide(0.09 g, 0.21 mmol) in CH₂ Cl₂ (1 mL) and pyridine.(1 mL) at 0° C. wasadded trimethylacetyl chloride (0.027 mL, 0.22 mmol). The solution wasallowed to warm to ambient temperature with stirring. After 16 hours,the reaction mixture was partitioned between ethyl acetate and diluteHCl. The organic layer was dried over Na₂ SO₄ and concentrated in vacuo.The resulting oil was purified by flash chromatography on silica gel toafford 0.038 g (40% yield) ofN-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-hydroxy4-((1,1-dimethylethyl)carbonyl)oxybenzamideas a white solid; NMR(DMSO-d₆) 12.2 (s, 1), 10.8 (s, 1), 10.4 (s, 1),8.3 (s, 1), 8.2 (d, 1), 8.0 (d, 1), 7.6-7.7 (m, 4), 7.4 (t, 2), 7.1 (t,1), 1.3 (s, 9) ppm.

B. Other compounds of the invention may be prepared by methods similarto those described in this Example and by methods known to those ofordinary skill in the art.

EXAMPLE 46

This example illustrates the preparation of representativepharmaceutical compositions for oral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,N-(5-chloropyridin-2-yl)-2-[((4-((pyridinium-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide:

    ______________________________________                                        A.      Ingredients     % wt./wt.                                             ______________________________________                                        Compound of the invention                                                                         20.0%                                                       Lactose 79.5%                                                                 Magnesium stearate 0.5%                                                     ______________________________________                                    

The above ingredients are mixed and dispensed into hard-shell gelatincapsules containing 100 mg each, one capsule would approximate a totaldaily dosage.

    ______________________________________                                        B.      Ingredients     % wt./wt.                                             ______________________________________                                        Compound of the invention                                                                         20.0%                                                       Magnesium stearate 0.9%                                                       Starch 8.6%                                                                   Lactose 69.6%                                                                 PVP (polyvinylpyrrolidine) 0.9%                                             ______________________________________                                    

The above ingredients with the exception of the magnesium stearate arecombined and granulated using water as a granulating liquid. Theformulation is then dried, mixed with the magnesium stearate and formedinto tablets with an appropriate tableting machine.

    ______________________________________                                        C.     Ingredients                                                            ______________________________________                                        Compound of the invention                                                                            0.1     g                                                Propylene glycol 20.0 g                                                       Polyethylene glycol 400 20.0 g                                                Polysorbate 80 1.0 g                                                          Water qs. 100 mL                                                            ______________________________________                                    

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity ofwater is then added with stirring to provide 100 mL of the solutionwhich is filtered and bottled.

    ______________________________________                                        D.      Ingredients     % wt./wt.                                             ______________________________________                                        Compound of the invention                                                                         20.0%                                                       Peanut Oil 78.0%                                                              Span 60 2.0%                                                                ______________________________________                                    

The above ingredients are melted, mixed and filled into soft elasticcapsules.

    ______________________________________                                        E.    Ingredients        % wt./wt.                                            ______________________________________                                        Compound of the invention                                                                          1.0%                                                       Methyl or carboxymethyl cellulose 2.0%                                        0.9% saline q.s. 100 mL                                                     ______________________________________                                    

The compound of the invention is dissolved in the cellulose/salinesolution, filtered and bottled for use.

EXAMPLE 47

This example illustrates the preparation of a representativepharmaceutical formulation for parenteral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide:

    ______________________________________                                        Ingredients                                                                   ______________________________________                                        Compound of the invention                                                                           0.02    g                                                 Propylene glycol 20.0 g                                                       Polyethylene glycol 400 20.0 g                                                Polysorbate 80 1.0 g                                                          0.9% Saline solution q.s. 100 mL                                            ______________________________________                                    

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity of0.9% saline solution is then added with stirring to provide 100 mL ofthe I.V. solution which is filtered through a 0.2 m membrane filter andpackaged under sterile conditions.

EXAMPLE 48

This example illustrates the preparation of a representativepharmaceutical composition in suppository form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide:

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                        1.0%                                                         Polyethylene glycol 1000 74.5%                                                Polyethylene glycol 4000 24.5%                                              ______________________________________                                    

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

EXAMPLE 49

This example illustrates the preparation of a representativepharmaceutical formulation for insufflation containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-acetoxyethoxy)-5-chlorobenzamide:

    ______________________________________                                        Ingredients           % wt./wt.                                               ______________________________________                                        Micronized compound of the invention                                                                1.0%                                                      Micronized lactose 99.0%                                                    ______________________________________                                    

The ingredients are milled, mixed, and packaged in an insufflatorequipped with a dosing pump.

EXAMPLE 50

This example illustrates the preparation of a representativepharmaceutical formulation in nebulized form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(dihydro-4(H)-1,3-oxazin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide:

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                        0.005%                                                       Water 89.995%                                                                 Ethanol 10.000%                                                             ______________________________________                                    

The compound of the invention is dissolved in ethanol and blended withwater. The formulation is then packaged in a nebulizer equipped with adosing pump.

EXAMPLE 51

This example illustrates the preparation of a representativepharmaceutical formulation in aerosol form containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,N-(4-chlorophenyl)-2-[((4-((N'-methyl-N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide:

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                        0.10%                                                        Propellant 11/12 98.90%                                                       Oleic acid 1.00%                                                            ______________________________________                                    

The compound of the invention is dispersed in oleic acid and thepropellants. The resulting mixture is then poured into an aerosolcontainer fitted with a metering valve.

EXAMPLE 52 (In vitro assay for Factor Xa and Thrombin)

This assay demonstrates the activity of the compounds of the inventiontowards factor Xa, thrombin and tissue plasminogen activator. Theactivities were determined as an initial rate of cleavage of the peptidep-nitroanilide by the enzyme. The cleavage product, p-nitroaniline,absorbs at 405 nm with a molar extinction coefficient of 9920 M⁻¹ cm⁻¹.

Reagents and Solutions:

Dimethyl sulfoxide (DMSO) (Baker analyzed grade).

Assay buffer:

50 mM TrisHCl, 150 mM NaCl, 2.5 mM CaCl₂, and

0.1% polyethylene glycol 6000, pH 7.5.

Enzymes (Enzyme Research Lab.):

1. Human factor Xa stock solution: 0.281 mg/mL in assay buffer, storedat -80° C. (working solution (2X): 106 ng/mL or 2 nM in assay buffer,prepare prior to use).

2. Human thrombin stock solution: Concentration as specified by thesupplier, stored at -80° C. (working solution (2X): 1200 ng/mL or 32 nMin assay buffer, prepare prior to use).

3. Human tissue plasminogen activator (tPA) (Two chains, Sigma orAmerican Diagnostica Inc.) stock solution: Concentration as specified bythe supplier, stored at -80° C. (working solution (2X): 1361 ng/mL or 20nM in assay buffer, prepare prior to use).

Chromogenic substrates (Pharmacia Hepar Inc.):

1. S2222 (FXa assay) stock solution: 6 mM in deionized H₂ O, store at 4°C. (working solution (4X): 656 μM in assay buffer).

2. S2302 (Thrombin assay) stock solution: 10 mM in deionized H₂ O,stored at 4° C. (working solution (4X): 1200 μM in assay buffer).

3. S2288 (tPA assay) stock solution: 10 mM in deionized H₂ O, stored at4° C. (working solution (4X): 1484 μM in assay buffer for Sigma tPA, or1120 ,μM for American Diagnostica tPA).

Standard inhibitor compound stock solution:

5 mM in DMSO, stored at -20° C.

Test compounds (compounds of the invention) stock solutions:

10 mM in DMSO, stored at -20° C.

Assay procedure:

Assays were performed in 96-well microtiter plates in a total volume of200 μl. Assay components were in final concentration of 50 mM TrisHCl,150 mM NaCl, 2.5 mM CaCl₂, 0.1 % polyethylene glycol 6000, pH 7.5, inthe absence or presence of the standard inhibitor or the test compoundsand enzyme and substrate at following concentrations: (1) 1 nM factor Xa(0.1 nM or 0.2 nM factor Xa for compounds with K_(i) Xa in low picomolarrange) and 164 μM S2222; (2) 16 nM thrombin and 300 μM S2302; and (3) 10nM tPA and 371 μM or 280 μM S2288. Concentrations of the standardinhibitor compound in the assay were from 5 μM to 0.021 μM in 1 to 3dilution. Concentration of the test compounds in the assay typicallywere from 10 μM to 0.041 μM in 1 to 3 dilution. For potent testcompounds, the concentrations used in the factor Xa assay were furtherdiluted 100 fold (100 nM to 0.41 nM) or 1000 fold (10 nM to 0.041 nM).All substrate concentrations used are equal to their Km values under thepresent assay conditions. Assays were performed at ambient temperature.

The first step in the assay was the preparation of 10 mM test compoundstock solutions in DMSO (for potent test compounds, 10 mM stocksolutions were further diluted to 0.1 or 0.01 mM for the factor Xaassay), followed by the preparation of test compound working solutions(4X) by a serial dilutions of 10 mM stock solutions with Biomek 1000 in96 deep well plates as follows:

(a) Prepare a 40 μM working solution by diluting the 10 mM stock 1 to250 in assay buffer in 2 steps: 1 to 100, and 1 to 2.5.

(b) Make another five serial dilutions (1:3) of the 40 μM solution (600μL for each concentration). A total of six diluted test compoundsolutions were used in the assay.

Standard inhibitor compound (5 mM stock) or DMSO (control) went throughthe same dilution steps as those described above for test compounds.

The next step in the assay was to dispense 50 μL of the test compoundworking solutions (4X) (from 40 μM to 0.164 μM) in duplicate tomicrotiter plates with Biomek. To this was added 100 μL of enzymeworking solution (2X) with Biomek. The resulting solutions wereincubated at ambient temperature for 10 minutes.

To the solutions was added 50 μL of substrate working solution (4X) withBiomek.

The enzyme kinetics were measured at 405 nm at 10 seconds intervals forfive minutes in a THERMOmax plate reader at ambient temperature. When alower concentration of factor Xa was needed in the factor Xa assay, theenzyme kinetics were measured for fifteen minutes (0.2 nM factor Xa) orthirty minutes (0.1 nM factor Xa) at ambient temperature.

Calculation of K_(i) of the Test compounds

Enzyme initial rates were calculated as mOD/min based on the first twominutes readings. The IC₅₀ values were determined by fifting the data tothe log-logit equation (linear) or the Morrison equation (non-linear)with an EXCEL spread-sheet. K_(i) values were then obtained by dividingthe IC₅₀ by 2. Routinely, K_(i) (factor Xa) values less than 3 nM werecalculated from the Morrison equation.

Compounds of the invention, when tested in this assay, demonstrated theselective ability to inhibit human factor Xa and human thrombin.

EXAMPLE 53 (In vitro assay for Human Prothrombinase)

This assay demonstrates the ability of the compounds of the invention toinhibit prothrombinase. Prothrombinase (PTase) catalyzes the activationof prothrombin to yield fragment 1.2 plus thrombin with meizothrombin asthe intermediate. This assay is an end point assay. Activity of theprothrombinase is measured by activity of thrombin (one of the reactionproducts) or by the amount of thrombin formed/time based on a thrombinstandard curve (nM vs mOD/min). For determination of IC₅₀ (PTase) of thecompounds of the invention, PTase activity was expressed by thrombinactivity (mOD/min).

Materials:

Enzymes:

1. Human factor Va (Haematologic Technologies Inc., Cat# HCVA-0110)working solution: 1.0 mg/mL in 50% glycerol, 2 mM CaCl₂, stored at -20°C.

2. Human factor Xa (Enzyme Res. Lab. cat# HFXal011) working solution:0.281 mg/mL in assay buffer (without BSA), stored at -80° C.

3. Human prothrombin (Fll) (Enzyme Res. Lab., Cat# HP1002) workingsolution: Diluted Fll to 4.85 mg/mL in assay buffer (without BSA),stored at -80° C.

Phospholipid (PCPS) vesicles

PCPS vesicles (80%PC, 20%PS) were prepared by modification of the methodreported by Barenholz et al., Biochemistry (1977), Vol. 16, pp.2806-2810.

Phosphatidyl serine (Avanti Polar Lipids, Inc., Cat#840032)

10 mg/mL in chloroform, purified from brain, stored -20° C. undernitrogen or argon.

Phosphatidyl Choline (Avanti Polar Lipids, Inc., Cat# 850457)

50 mg/ml in chloroform, synthetic 16:0-18:1 Palmitoyl-Oleoyl, stored at-20° C. under nitrogen or argon.

Spectrozyme-TH (American Diagnostica Inc., Cat# 238L, 50 μmoles, storedat ambient temperature) working solution: Dissolved 50 μmoles in 10 mLdH₂ O.

BSA (Sigma Chem Co., Cat# A-7888, FractionV, RIA grade).

Assay buffer: 50 mM TrisHCl, pH 7.5,150 mM NaCl, 2.5 mM CaCl₂, 0.1% PEG6000 (BDH), 0.05% BSA (Sigma, Fr.V, RIA grade).

For one plate assay, prepare the following working solutions:

1. Prothrombinase complex:

(a) 100 μM PCPS (27.5 μL of PCPS stock (4.36 mM) diluted to final 1200μL with assay buffer.

(b) 25 nM Human factor Va: 5.08 μL of Va stock(1 mg/mL) was diluted tofinal 1200 μL with assay buffer.

(c) 5 pM Human factor Xa: Dilute factor Xa stock (0.281 mg/mL)1:1,220,000 with assay buffer. Prepare at least 1200 μL.

Combine equal volumes (1100 μL) of each component in the order of PCPS,Va and Xa. Use immediately or store in ice (bring to ambient temperaturebefore use).

2. 6 μM Human prothrombin (Fll): dilute 124 μL of Fll stock (4.85 mg/mL)to final 1400 μL with assay buffer.

3. 20 mM EDTA/Assay buffer: 0.8 mL of 0.5 M EDTA (pH 8.5) plus 19.2 mLassay buffer.

4. 0.2 mM Spectrozyme-TH/EDTA buffer: 0.44 mL of SPTH stock (5 mM) plus10.56 mL of 20 mM EDTA/assay buffer.

5. Test compounds (compounds of the invention):

Prepare a working solution (5X) from 10 mM stock (DMSO) and make aseries of 1:3 dilution. Compounds were assayed at 6 concentrations induplicate.

Assay conditions and procedure

Prothrombinase reaction was performed in final 50 μL of mixturecontaining PTase (20 μM PCPS, 5 nM hFVa, and 1 pM hFXa), 1.2 μM humanfactor ll and varied concentration of the test compounds (5 μM to 0.021μM or lower concentration range). Reaction was started by addition ofPTase and incubated for 6 minutes at ambient temperature. Reaction wasstopped by addition of EDTA/buffer to final 10 mM. Activity of thrombin(product) was then measured in the presence of 0.1 mM of Spectrozyme-THas substrate at 405 nm for 5 minutes (10 seconds intervals) at ambienttemperature in a THEROmax microplate reader. Reactions were performed in96-well microtiter plates.

In the first step of the assay, 10 μL of diluted test compound (5X) orbuffer was added to the plates in duplicate. Then 10 μL of prothrombin(hFll) (5X) was added to each well. Next 30 μL PTase was added to eachwell, mix for about 30 seconds. The plates were then incubated atambient temperature for 6 minutes.

In the next step, 50 μL of 20 mM EDTA (in assay buffer) was added toeach well to stop the reaction. The resulting solutions were then mixedfor about 10 seconds. Then 100 μL of 0.2 mM spectrozyme was added toeach well. The thrombin reaction rate was then measured at 405 nm for 5minutes at 10 seconds intervals in a Molecular Devices microplatereader.

Calculations

Thrombin reaction rate was expressed as mOD/min. using OD readings fromthe five minute reaction. IC₅₀ values were calculated with the log-logitcurve fit program.

The compounds of the invention demonstrated the ability to inhibitpro-hrombinase when tested in this assay.

EXAMPLE 54 (In vivo assay)

The following assay demonstrates the ability of the compounds to act asanti-coagulants.

Male rats (250-330 g) were anesthetized with sodium pentobarbital (90mg/kg, i.p.) and prepared for surgery. The left carotid artery wascannulated for the measurement of blood pressure as well as for takingblood samples to monitor clotting variables (prothrombin time (PT) andactivated partial thromboplastin time (aPTT)). The tail vein wascannulated for the purpose of administering the test compounds (i.e.,the compounds of the invention and standards) and the thromboplastininfusion. The abdomen was opened via a mid-line incision and theabdominal vena cava was isolated for 2-3 cm distal to the renal vein.All venous branches in this 2-3 cm segment of the abdominal vena cavawere ligated. Following all surgery, the animals were allowed tostabilize prior to beginning the experiment. Test icompounds wereadministered as an intravenous bolus (t=0). Three minutes later (t=3), a5-minute infusion of thromboplastin was begun. Two minutes into theinfusion (t=5), the abdominal vena cava was ligated at both the proximaland distal ends. The vessel was left in place for 60 minutes, afterwhich it was excised from the animal, slit open, the clot (if any)carefully removed, and weighed. Statistical analysis on the results wasperformed using a Wilcoxin-matched-pairs signed rank test.

The compounds of the invention, when tested in this assay, demonstratedthe ability to inhibit the clotting of the blood.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound of formula (I): ##STR55## wherein: Ais =N--;m is 1 to 3; n is 1 to 4; D is --N(R⁵)--C(Z)-- or--N(R⁵)--S(O)_(p) -- (where p is 0 to 2; Z is oxygen, sulfur or H₂ ; andthe nitrogen atom is directly bonded to the phenyl ring having the R¹and R² substituents); E is --C(Z)--N(R⁵)-- or --S(O)_(p) --N(R⁵)--(where p is 0 to 2; Z is oxygen, sulfur or H₂ ; and the nitrogen atomcan be bonded to the phenyl ring having the R¹ and the R² substituentsor to the aromatic ring having the R⁴ substituent); each R¹ isindependently hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano,--OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵, --C(O)N(R⁵)R⁶,--N(R⁵)R⁶, --O--C(O)R⁵, or --N(R⁵)--CH(R¹²)--C(O)OR⁵ ; or two adjacentR¹, s together with the carbons to which they are attached form aheterocyclic ring fused to the phenyl ring wherein the heterocyclic ringis optionally substituted by one or more substituents selected from thegroup consisting of alkyl, aryl and aralkyl; R² is hydrogen, alkyl,aryl, aralkyl, halo, haloalkyl, cyano, --OR⁵, --S(O)_(p) --R⁹ (where pis 0 to 2), --C(O)OR⁵, --OC(O)--R⁵, --C(O)N(R⁵)R⁶, --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸ --N(R¹⁰)R¹¹, --C(R⁷)H--OR⁵,--C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--S(O)_(p) --R⁹ (where p is 0 to 2),--C(R⁷)H--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --O--R⁸ --S(O)_(p)--R⁹ (where p is 0 to 2), --C(R⁷)H--N(R⁵)R⁶, --C(R⁷)H--R⁸ --N(R⁵)R⁶,--O--R⁸ --CH(OH)--CH₂ --N(R¹⁰)R¹¹, --O--R⁸ --N(R¹⁰)R¹¹, --O--R⁸--O--C(O)R⁵, --O--R⁸ --CH(OH)--CH₂ --OR⁵, --O--(R⁸ --O)_(t) --R⁵ (wheret is 1 to 6), --O--(R⁸ --O)_(t) --R¹⁹ (where t is 1 to 6), --O--R⁸--C(O)R5, --O--R⁸ --C(O)R¹⁹, --O--R⁸ --C(O)OR⁵, --N(R⁵)--R⁸ --N(R¹⁰)R¹¹,--S(O)_(p) --R⁸ --N(R⁵)R⁶ (where p is 0 to 2), --S(O)_(p) --R⁸ --C(O)OR⁵(where p is 0 to 2), or --N(R⁵)--CH(R¹²)--C(O)OR⁵ ; R³ is a radical offormula (i): ##STR56## where: r is 1 or2;R¹³ is hydrogen, alkyl, halo,haloalkyl, --N(R⁵)R⁶, --C(R⁷)H--N(R⁵)R⁶, O--R⁵, --R⁸ --OR⁵, --S(O)_(p)--R⁸ --N(R⁵)R⁶ (where p is 0 to 2) or heterocyclylalkyl (where theheterocyclic ring is optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, aralkyl, nitro andcyano); and each R¹⁴ is independently hydrogen, alkyl, halo, formyl,acetyl, cyano, --R⁸ --CN, --N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸--N(R¹⁰)R¹¹, --C(R⁷)H--N.sup.⊕ (R⁹)(R¹⁶)₂, --C(R⁷)H--R⁸ --N.sup.⊕(R⁹)(R¹⁶)₂, --C(O)OR⁵, --C(R⁷)H--C(O)OR⁵, --C(R⁷)H--R⁸ --C(O)OR⁵, --OR⁵,--C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--O--R¹⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --C(R⁷)H--S(O)_(p) --R¹⁵ (where p is 0 to 2),--C(R⁷)H--R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2), --S(O)_(p) --N(R⁵)R⁶(where p is 0 to 2), --C(O)N(R⁵)R⁶, --C(R⁷)H--C(O)N(R⁵)R⁶, --C(R⁷)H--R⁸--C(O)N(R⁵)R⁶, --C(R⁷)H--N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--R⁸ --N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --C(R⁷)H--R⁸--O--(R⁸ --O)_(t) --R⁵ (where t is I to 6), --O--R⁸ --CH(OH)--CH₂ --OR⁵,--C(R⁷)H--O--R⁸ --CH(OH)--CH₂ --OR⁵, --C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t)--CH₂ --OR⁵ (where t is 1 to 6), --C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)--C(N R¹⁷)--R¹⁰,--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--O--N(R⁵)R⁶,heterocyclyl (wherein the heterocyclyl radical is not attached to theradical of formula (i) through a nitrogen atom and is optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (whereinthe heterocyclyl radical is not attached to the alkyl radical through anitrogen atom and is optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); each R⁴is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, or --R⁸ --N(R⁵)R⁶ ; R⁵ and R⁶ areeach independently hydrogen, alkyl, aryl or aralkyl; each R⁷ isindependently hydrogen or alkyl; each R⁸ is independently a straight orbranched alkylene, alkylidene or alkylidyne chain; each R⁹ isindependently alkyl, aryl or aralkyl; R¹⁰ and R¹¹ are each independentlyhydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, --R⁸ --CN,--OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸--S(O)p--R¹⁵ (where p is 0 to 2), --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸ --C(O)NH₂, --C(S)NH₂,--C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸ --C(O)--N(R⁵)R¹⁵,--C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸ --N(R⁵)--C(O)R¹⁵,--C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)=C(R¹⁸)R¹⁰, --R⁸ --N(R⁵)-P(O)(OR⁵)₂,cycloalkyl (optionally substituted by one or more substituents selectedfrom the group consisting of alkyl, halo and --OR⁵), heterocyclyl(optionally substituted by one or more substituents selected from alkyl,aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵,--S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0to 2), --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸--OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p)--R⁹ (where p is 0 to 2), --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); or R¹⁰ and R¹¹together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸ --CN, =N(R¹⁷), --OR⁵,--C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶,--R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), --S(O)p--R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1to 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶); R¹² isa side chain of an α-amino acid; each R¹⁵ is independently alkyl,cycloalkyl, haloalkyl, aryl, aralkyl, --R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵,--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), or heterocyclylalkyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --R⁸--OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶); or R⁵ and R¹⁵ togetherwith the nitrogen to which they are attached form a N-heterocyclic ringcontaining zero to three additional hetero atoms, where theN-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl; each R¹⁶ isindependently alkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁸ --N(R⁵)R⁶,cycloalkyl (optionally substituted by one or more substituents selectedfrom the group consisting of alkyl, halo and --OR⁵), heterocyclyl(optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); or both R^(16') s together with thenitrogen to which they are attached (and wherein the R⁹ substituent isnot present) form an aromatic N-heterocyclic ring containing zero tothree additional hetero atoms, where the N-heterocyclic ring isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, aryl, aralkyl, --OR⁵, --C(O)OR⁵, --R⁸--C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t)--R⁵ (where t is 1 to 6), and --(R⁸ --O)_(t) --R⁵ (where t is 1 to 6);each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶ ; R¹⁸ is hydrogen, alkyl, aryl, aralkyl, cyano,--C(O)OR⁵, or --NO₂ ; and each R¹⁹ is cycloalkyl, haloalkyl, --R⁸ --OR⁵,--R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --R⁸ --C(O)N(R⁵)R⁶, heterocyclyl(optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); as a single stereoisomer or a mixturethereof; or a pharmaceutically acceptable salt thereof.
 2. Apharmaceutical composition useful in treating a human having adisease-state characterized by thrombotic activity, which compositioncomprises a pharmaceutically acceptable excipient and a therapeuticallyeffective amount of a compound of formula (I): ##STR57## wherein: A is=N--;m is 1 to 3; n is 1 to 4; D is --N(R⁵)--C(Z)-- or --N(R⁵)--S(O)_(p)--(where p is 0 to 2; Z is oxygen, sulfur or H₂ ; and the nitrogen atomis directly bonded to the phenyl ring having the R¹ and R²substituents); E is --C(Z)--N(R⁵)-- or --S(O)_(p) --N(R⁵)--(where p is 0to 2; Z is oxygen, sulfur or H₂ ; and the nitrogen atom can be bonded tothe phenyl ring having the R¹ and the R² substituents or to the aromaticring having the R⁴ substituent); each R¹ is independently hydrogen,alkyl, aryl, aralkyl, halo, haloalkyl, cyano, --OR⁵, --S(O)_(p) --R⁹(where p is 0 to 2), --C(O)OR⁵, --C(O)N(R⁵)R⁶, --N(R⁵)R⁶, --O--C(O)R⁵,or --N(R⁵)--CH(R¹²)--C(O)OR⁵ ; or two adjacent R¹, s together with thecarbons to which they are attached form a heterocyclic ring fused to thephenyl ring wherein the heterocyclic ring is optionally substituted byone or more substituents selected from the group consisting of alkyl,aryl and aralkyl; R² is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl,cyano, --OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵,--OC(O)--R⁵, --C(O)N(R⁵)R⁶, --N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹,--C(R⁷)H--R⁸ --N(R¹⁰)R¹¹, --C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵,--C(R⁷)H--S(O)_(p) --R⁹ (where p is 0 to 2), --C(R⁷)H--R⁸ --S(O)_(p)--R⁹ (where p is 0 to 2), --O--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--C(R⁷)H--N(R⁵)R⁶, --C(R⁷)H--R⁸ --N(R⁵)R⁶, --O--R⁸ --CH(OH)--CH₂--N(R¹⁰)R¹¹, --O--R⁸ --N(R¹⁰)R¹¹, --O--R⁸ --O--C(O)R⁵, --O--R⁸--CH(OH)--CH₂ --OR⁵, --O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--O--(R⁸ --O)_(t) --R¹⁹ (where t is 1 to 6), --O--R⁸ --C(O)R⁵, --O--R⁸--C(O)R¹⁹, --O--R⁸ --C(O)OR⁵, --N(R⁵)--R⁸ --N(R¹⁰)R¹¹, --S(O)_(p) --R⁸--N(R⁵)R⁶ (where p is 0 to 2), --S(O)p--R⁸ --C(O)OR⁵ (where p is 0 to2), or --N(R⁵)--CH(R¹²)--C(O)OR⁵ ; R³ is a radical of formula (i):##STR58## where: r is 1 or 2;R¹³ is hydrogen, alkyl, halo, haloalkyl,--N(R⁵)R⁶, --C(R⁷)H--N(R⁵)R⁶, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R⁸--N(R⁵)R⁶ (where p is 0 to 2) or heterocyclylalkyl (where theheterocyclic ring is optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, aralkyl, nitro andcyano); and each R¹⁴ is independently hydrogen, alkyl, halo, formyl,acetyl, cyano, --R⁸ --CN, --N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸--N(R¹⁰)R¹¹, --C(R7)H--N.sup.⊕ (R⁹)(R¹⁶)₂, --C(R⁷)H--R⁸ --N.sup.⊕(R⁹)(R¹⁶)₂, --C(O)OR⁵, --C(R⁷)H--C(O)OR⁵, --C(R⁷)H--R⁸ --C(O)OR⁵, --OR⁵,--C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--O--R¹⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --C(R⁷)H--S(O)_(p) --R¹⁵ (where p is 0 to 2),--C(R⁷)H--R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2), --S(O)_(p) --N(R⁵)R⁶(where p is 0 to 2), --C(O)N(R⁵)R⁶, --C(R⁷)H--C(O)N(R⁵)R⁶, --C(R⁷)H--R⁸--C(O)N(R⁵)R⁶, --C(R⁷)H--N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--R⁸ --N(R⁵)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --C(R⁷)H--R⁸--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --O--R⁸ --CH(OH)--CH₂ --OR⁵,--C(R⁷)H--O--R⁸ --CH(OH)--CH₂ --OR⁵, --C(R⁷)H--N(R⁵)--R⁸ -[CH(OH)]_(t)--CH₂ --OR⁵ (where t is 1 to 6), --C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰,--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--O--N(R⁵)R⁶,heterocyclyl (wherein the heterocyclyl radical is not attached to theradical of formula (i) through a nitrogen atom and is optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (whereinthe heterocyclyl radical is not attached to the alkyl radical through anitrogen atom and is optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); each R⁴is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, or --R⁸ --N(R⁵)R⁶ ; R⁵ and R⁶ areeach independently hydrogen, alkyl, aryl or aralkyl; each R⁷ isindependently hydrogen or alkyl; each R⁸ is independently a straight orbranched alkylene, alkylidene or alkylidyne chain; each R⁹ isindependently alkyl, aryl or aralkyl; R¹⁰ and R¹¹ are each independentlyhydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, --R⁸ --CN,--OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --S(O)_(p)--R¹⁵ (where p is 0 to 2), --N(R⁵)R⁶, --R⁸ --N(R⁵)R, --R⁸ --C(O)OR⁵,--C(O)--R¹⁵, --C(O)NH₂, --R⁸ --C(O)NH₂, --C(S)NH₂, --C(O--S--R⁵,--C(O)--N(R⁵)R¹⁵, --R⁸ --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, --R⁸--N(R⁵)--C(O)H, --R⁸ --N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶,--C(N(R⁵)R⁶)=C(R¹⁸)R¹⁰, --R⁸ --N(R⁵)-P(O)(OR⁵)₂, cycloalkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo and --OR⁵), heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸--OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p)--R⁹ (where p is 0 to 2), --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹ (where pis 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶ and--C(O)N(R⁵)R⁶); or R¹⁰ and R¹¹ together with the nitrogen to which theyare attached form a N-heterocyclic ring containing zero to threeadditional hetero atoms, where the N-heterocyclic ring is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano,--R⁸ --CN, =N(R¹⁷), --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸--N(R⁵)R⁶, --C(O)N(R⁵)R⁶, --R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶,--C(O)R⁵, --C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --S(O)_(p) --R⁹(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸--O)_(t) --R⁵ (where t is 1 to 6), and heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶, and --C(O)N(R⁵)R⁶); R¹² is a side chain of an α-amino acid;each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶); or R⁵ and R¹⁵ together with the nitrogen to which theyare attached form a N-heterocyclic ring containing zero to threeadditional hetero atoms, where the N-heterocyclic ring is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino,--OR⁵, --C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl; each R¹⁶ is independently alkyl, aryl, aralkyl,--R⁸ --OR⁵, --R⁸ --N(R⁵)R⁶, cycloalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); or bothR^(16') s together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --C(O)OR⁵, R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)R⁵,--C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸ --O)_(t) --R⁵(where t is 1 to 6); each R¹⁷ is independently hydrogen, alkyl, aryl,aralkyl, cyano, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵,--C(O)--N(R⁵)R⁶, or --R⁸ --C(O)--N(R⁵)R⁶ ; R¹⁸ is hydrogen, alkyl, aryl,aralkyl, cyano, --C(O)OR⁵, or --NO₂ ; and each R¹⁹ is cycloalkyl,haloalkyl, --R⁸ --OR⁵, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --R⁸--C(O)N(R⁵)R⁶, heterocyclyl (optionally substituted by alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶),or heterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); as a singlestereoisomer or a mixture thereof; or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 1 wherein:A is =N--; m is 1 to 3; n is1 to 4; D is --N(R⁵)--C(Z)-- (where Z is oxygen, sulfur or H₂, and R⁵ ishydrogen or alkyl); E is --C(Z)--N(R⁵)-- (where Z is oxygen, sulfur orH₂, R⁵ is hydrogen or alkyl, and the nitrogen is attached to thepyridinyl ring); R¹ is halo or haloalkyl; R² is --N(R¹⁰)R¹¹, --O--R⁸--S(O)p--R⁹ (where p is 0), --O--R⁸ --C(O)OR⁵, --O--(R⁸ --O)_(t) --R⁵(where t is 1) or --O--R⁸ --N(R¹⁰)R¹¹ where:each R⁵ is independentlyhydrogen or alkyl; each R⁸ is independently a straight or branchedalkylene chain; R⁹ is alkyl; and R¹⁰ and R¹¹ are each independentlyhydrogen, alkyl, or --R⁸ --O--R⁵ (where R⁸ is a straight or branchedalkylene chain and R⁵ is hydrogen or alkyl); or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached form a N-heterocyclic ringcontaining zero to one additional hetero atoms, where the N-heterocyclicring is optionally substituted by alkyl; R³ is a radical of the formula(i): ##STR59## where r is 1; R¹³ is halo; andR¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹where:R⁷ is hydrogen; and R¹⁰ and R¹¹ together with the nitrogen towhich they are attached form piperazinyl optionally substituted by oneor more substituents selected from the group consisting of alkyl and--C(O)R⁵ ; and R⁴ is hydrogen or halo.
 4. The compound of claim 3wherein:m is 1; n is 1; D is --N(H)--C(O)--; E is --C(O)--N(H)-- (wherethe nitrogen is bonded to the 2-position of the pyridinyl ring); R¹ ishalo in the 5-position; R² is --N(R¹⁰)R¹¹, --O--R⁸ --S(O)_(p) --R⁹(where p is 0), --O--R⁸ --C(O)OR⁵, --O--(R⁸ --O)_(t) --R⁵ (where t is 1)or --O--R⁸ --N(R¹⁰)R¹¹ where:each R⁵ is independently hydrogen, methylor ethyl; each R⁸ is independently a methylene, ethylene or propylenechain; R⁹ is methyl or ethyl; and R¹⁰ and R¹¹ are each independentlyhydrogen, methyl, ethyl, or --R⁸ --O--R⁵ (where R⁸ is ethylene and R⁵ ishydrogen, methyl or ethyl); or R¹⁰ and R¹¹ together with the nitrogen towhich they are attached form a N-heterocyclic ring containing zero toone additional hetero atoms, where the N-heterocyclic ring is optionallysubstituted by alkyl; R³ is a radical of the formula (i): ##STR60##where r is 1; R¹³ is chloro; andR¹⁴ is in the 4-position and is--C(R⁷)H--N(R¹⁰)R¹¹ where:R⁷ is hydrogen; and R¹⁰ and R¹¹ together withthe nitrogen to which they are attached form piperazinyl optionallysubstituted by methyl or ethyl; and R⁴ is hydrogen, bromo or chloro inthe 5-position.
 5. The compound of claim 4 wherein:R¹ is chloro; R² is--O--R⁸ --S(O)_(p) --R⁹ (where p is 0), --O--R⁸ --C(O)OR⁵ or --O--(R⁸--O)_(t) --R⁵ (where t is 1 or 2) where:each R⁵ is independentlyhydrogen, methyl or ethyl; each R⁸ is independently a methylene,ethylene or propylene chain; and R⁹ is methyl or ethyl.
 6. The compoundof claim 5 which is selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(methylthio)methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-ethoxyethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,andN-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide.7. The compound of claim 4 whereinR¹ is chloro; and R² is --N(R¹⁰)R¹¹ or--O--R⁸ --N(R¹⁰)R¹¹ where:R⁸ is a methylene, ethylene or propylenechain; and R¹⁰ and R¹¹ are each independently hydrogen, methyl, ethyl,or --R⁸ --O--R⁵ (where R⁸ is ethylene and R⁵ is hydrogen, methyl orethyl).
 8. The compound of claim 7 which is selected from the groupconsistingof:N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(N'-methyl-N'-(2-hydroxyethyl)amino)propoxy)-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-amino-5-chlorobenzamide.9. The compound of claim 4 whereinR¹ is chloro; R² is --N(R¹⁰)R¹¹ or--O--R⁸ --N(R¹⁰)R¹¹ where:R⁸ is methylene, ethylene or propylene; andR¹⁰ and R¹¹ together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to one additional hetero atoms,where the N-heterocyclic ring is optionally substituted by alkyl and isselected from the group consisting of morpholinyl, piperazinyl,pyrrolidinyl or imidazolyl.
 10. The compound of claim 9 selected fromthe group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-morpholinylpropoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolidin-1-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(imidazol-1-yl)propoxy)-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide.11. The compound of claim 1 wherein:A is =N--; m is 1 to 3; n is 1 to 4;D is --N(R⁵)--C(Z)--(where Z is oxygen, sulfur or H₂, and R⁵ is hydrogenor alkyl); E is --C(Z)--N(R⁵)--(where Z is oxygen, sulfur or H₂, R⁵ ishydrogen or alkyl, and the nitrogen is attached to the pyridinyl ring);R¹ is halo or haloalkyl; R² is hydrogen, haloalkyl, or --OR⁵ where R⁵ ishydrogen or alkyl; R³ is a radical of the formula (i): ##STR61## where ris 1; R¹³ is halo; andeach R¹⁴ is independently hydrogen, alkyl, halo,formyl, acetyl, cyano, --R⁸ --CN, --N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹,--C(R⁷)H--R⁸ --N(R¹⁰)R¹¹, --C(R⁷)H--N.sup.⊕ (R⁹)(R¹⁶)₂, --C(R⁷)H--R⁸--N.sup.⊕ (R⁹)(R¹⁶)₂, --C(O)OR⁵, --C(R⁷)H--C(O)OR⁵, --C(R⁷)H--R⁸--C(O)OR⁵, --OR⁵, --C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--O--R¹⁵,--S(O)_(p) --R¹⁵ (where p is 0 to 2), --C(R⁷)H--S(O)_(p) --R¹⁵ (where pis 0 to 2), --C(R⁷)H--R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2),--S(O)_(p) --N(R⁵)R⁶ (where p is 0 to 2), -C(O)N(R⁵)R⁶,--C(R⁷)H--C(O)N(R⁵)R⁶, --C(R⁷)H--R⁸ --C(O)N(R⁵)R⁶, --C(R⁷)H--N(R⁵)--(R⁸-O)_(t) --R⁵ (where t is 1 to 6), --C(R⁷)H--R--N(R⁵)-(R⁸ --O)_(t) --R⁵(where t is 1 to 6), --C(R⁷)H--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--R⁸ --O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --O--R⁸--CH(OH)--CH₂ --OR⁵, --C(R⁷)H--O--R⁸ --CH(OH)--CH₂ --OR⁵,--C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t) --CH₂ --OR⁵ (where t is 1 to 6),--C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰,--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--O--N(R⁵)R⁶,heterocyclyl (wherein the heterocyclyl radical is not attached to theradical of formula (i) through a nitrogen atom and is optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (whereinthe heterocyclyl radical is not attached to the alkyl radical through anitrogen atom and is optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); where R⁵and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl; each R⁷is independently hydrogen or alkyl; each R⁸ is independently a straightor branched alkylene, alkylidene or alkylidyne chain; each R⁹ isindependently alkyl, aryl or aralkyl; R¹⁰ and R¹¹ are each independentlyhydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, --R⁸ --CN,--OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --S(O)_(p)--R¹⁵ (where p is 0 to 2), --N(R )R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,--C(O)--R¹⁵, --C(O)NH₂, --R⁸ --C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵,--C(O)--N(R⁵)R¹⁵, R⁸ --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, --R⁸--N(R⁵)--C(O)H, --R⁸ --N(R⁵)--C(O)R₁₅, --C(O)O--R --N(R⁸)R⁶,--C(N(R⁵)R⁶)=C(R¹⁸)R¹⁰, --R⁸ --N(R⁵)-P(O)(OR⁵)₂, cycloalkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo and --OR⁵), heterocyclyl (optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸--OR⁵, --C(O)OR⁵, --S(O)p--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹(where p is 0 to 2), --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)p--R⁹ (where p is 0 to 2), --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), whereR⁵and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl; each R⁸is independently a straight or branched alkylene, alkylidene oralkylidyne chain; each R⁹ is independently alkyl, aryl or aralkyl; eachR¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸--O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,heterocyclyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶),or heterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶),where R⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl,and each R⁸ is independently a straight or branched alkylene, alkylideneor alkylidyne chain; or R⁵ and R¹⁵ together with the nitrogen to whichthey are attached form a N-heterocyclic ring containing zero to threeadditional hetero atoms, where the N-heterocyclic ring is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino,--OR⁵, --C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl, whereeach R⁵ is hydrogen, alkyl, aryl or aralkyl;and R¹⁸ is hydrogen, alkyl, aryl, aralkyl, cyano, --C(O)OR⁵, or --NO₂ ;or R¹⁰ and R¹¹ together with the nitrogen to which they are attachedform a N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, halo,haloalkyl, aryl, aralkyl, oxo, nitro, cyano, --R⁸ --CN, =N(R¹⁷), --OR⁵,--C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶,--R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t) R⁵(where t is 1 to 6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1to 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶),whereR⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain; each R⁹ is independently alkyl, aryl or aralkyl; eachR¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵, --R⁸--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶, whereR⁵ and R⁶ are independently each hydrogen, alkyl,aryl or aralkyl, and each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain; each R¹⁶ is independentlyalkyl, aryl, aralkyl, --R --OR⁵, --R⁸ --N(R⁵)R⁶, cycloalkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo and --OR⁵), heterocyclyl (optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), whereR⁵ and R⁶ are independently eachhydrogen, alkyl, aryl or aralkyl, and each R⁸ is independently astraight or branched alkylene, alkylidene or alkylidyne chain; or bothR¹⁶, s together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)R⁵,--C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸ --O)_(t) --R⁵(where t is 1 to 6), whereR⁵ and R⁶ are independently each hydrogen,alkyl, aryl or aralkyl, and each R⁸ is independently a straight orbranched alkylene, alkylidene or alkylidyne chain; each R¹⁷ isindependently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵, --R⁸ --OR⁵,--C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸ --C(O)--N(R⁵)R⁶,whereR⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl,and each R⁸ is independently a straight or branched alkylene, alkylideneor alkylidyne chain; and R⁴ is hydrogen or halo.
 12. The compound ofclaim 11 wherein:m is 1; n is 1; D is --N(H)--C(O)--; E is--C(O)--N(H)-- (where the nitrogen is bonded to the 2-position of thepyridinyl ring); R² is hydrogen, haloalkyl, or --OR⁵ where R⁵ ishydrogen or alkyl; R³ is a radical of the formula (i): ##STR62## where ris 1; R¹³ is halo; andR is --C(R⁷)H--N(R¹⁰)R¹¹ where:R⁷ is hydrogen; R¹⁰and R¹¹ are each independently hydrogen, alkyl, haloalkyl, aryl,aralkyl, formyl, cyano, --R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2),--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸--C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵, --C(O)--N(R⁵)R⁵,--R--C(O)--N(R⁵)R¹⁵,--C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸--N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)=C(R¹⁸)R¹⁰, --R⁸--N(R⁵)-P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alky, aryl, aralkyl,halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)p--R⁹ (where pis 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶ or--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R⁹ (where p is 0 to 2), --R8--S(O)p--R⁹ (where p is 0 to 2), --N(R⁵)R⁶and --C(O)N(R⁵)R⁶), where R⁵ and R⁶ are each independently hydrogen,alkyl, aryl or aralkyl; each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain; each R⁹ is independentlyalkyl, aryl or aralkyl; each R¹⁵ is independently alkyl, cycloalkyl,haloalkyl, aryl, aralkyl, --R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶,--R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, heterocyclyl (optionally substituted byone or more substituents selected from the group consisting of alkyl,aryl, aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶,and --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), whereR⁵ and R⁶ are independently each hydrogen, alkyl,aryl or aralkyl, and each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain; or R⁵ and R¹⁵ together withthe nitrogen to which they are attached form a N-heterocyclic ringcontaining zero to three additional hetero atoms, where theN-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl, whereeach R⁵ ishydrogen, alkyl, aryl or aralkyl; and R¹⁸ is hydrogen, alkl, aryl,aralkyl, cyano, --C(O)OR⁵, or --NO₂ ; or R¹⁰ and R¹¹ together with thenitrogen to which they are attached form a N-heterocyclic ringcontaining zero to three additional hetero atoms, where theN-heterocylic ring is optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, aryl,aralkyl, oxo, nitro, cyano, --R⁸ --CN, =N(R¹⁷), --OR⁵, --C(O)OR⁵, --R⁸--C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, --R⁸ --C(O)N(R⁵)R⁶,--N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where pis 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and heterocyclyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), whereR⁵ and R⁶ are eachindependently hydrogen, alkyl, aryl or aralkyl; each R⁸ is independentlya straight or branched alkylene, alkylidene or alkylidyne chain; each R⁹is independently alkyl, aryl or aralkyl; each R¹⁷ is independentlyhydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵,--R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸ --C(O)--N(R⁵)R⁶ whereR⁵ and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and each R⁸ isindependently a straight or branched alkylene, alkylidene or alkylidynechain; and R⁴ is in the 5-position.
 13. The compound of claim 12wherein:R¹⁰ and R¹¹ are each independently hydrogen, alkyl, haloalkyl,aryl, aralkyl, formyl, cyano, --R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p)--R¹⁵ (where p is 0 to 2), --R⁸ --S(O)p--R¹⁵ (where p is 0 to 2),--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸--C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸--N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)=C(R¹⁸)R¹⁰, --R⁸--N(R⁵)-P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)p--R9 (where pis 0 to 2), --R⁸ --S(O)_(p) R⁹ (where p is 0 to 2), --N(R⁵)R⁶ or--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R9 (where p is 0 to 2), --R --S(O)p--R⁹ (where p is 0 to 2), --N(R⁵)R⁶and --C(O)N(R⁵)R⁶), whereR⁵ and R6 are each independently hydrogen,alkyl, aryl or aralkyl; each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain; each R⁹ is independentlyalkyl, aryl or aralkyl; each R¹⁵ is independently alkyl, cycloalkyl,haloalkyl, aryl, aralkyl, --R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶,--R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, heterocyclyl (optionally substituted byone or more substituents selected from the group consisting of alkyl,aryl, aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶,and --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R--OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶) whereR⁵ and R⁶ are independently each hydrogen, alkyl,aryl or aralkyl, and each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain; or R⁵ and R¹⁵ together withthe nitrogen to which they are attached form a N-heterocyclic ringcontaining zero to three additional hetero atoms, where theN-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl, whereeach R⁵ isindependently hydrogen, alkyl, aryl or aralkyl; and R¹⁸ is hydrogen,alkyl, aryl, aralkyl, cyano, --C(O)OR⁵, or --NO₂.
 14. The compound ofclaim 13 wherein:R¹⁰ is hydrogen, alkyl, or --R⁸ --OR⁵ ; and R¹¹ ishydrogen, alkyl or --R⁸ --OR⁵ ; where each R⁸ is independently astraight or branched alkylene chain, and each R⁵ is hydrogen or alkyl.15. The compound of claim 14 selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((Nmethyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'N'-di(2-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(3-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2,2-dimethyl-2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-ethoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(((2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--N'-methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-methylethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(ethylamino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-(diethylamino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.16. The compound of claim 13 wherein:R¹⁰ is hydrogen, alkyl, or --R⁸--N(R⁵)R⁶, and R¹¹ is --S(O)_(p) --R¹⁵ (where p is 0 to 2) or --R⁸--N(R⁵)R⁶ where:R⁵ and R⁶ are independently hydrogen or alkyl; each R⁸is independently a straight or branched alkylene, alkylidene oralkylidyne chain; and R¹⁵ is independently alkyl, cycloalkyl, haloalkyl,aryl, aralkyl, --R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸--N(R⁵)R⁶, --R⁸ --C(O)OR⁵, heterocyclyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶) whereR⁵ and R⁶ are independently each hydrogen, alkyl,aryl or aralkyl, and each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain.
 17. The compound of claim 16selected from the group consistingof.N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(methyl)sulfonyl--N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-((3,5-dimethylisoxazol4-yl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-((2-(4-hydroxypiperidin-1-yl)ethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((Nt-methyl--N'-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-aminoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--N'-(4-(dimethylamino)but-3-yn-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.18. The compound of claim 13 wherein:R10 is hydrogen, alkyl or --R⁸--OR⁵ ; and R¹¹ is formyl, cyano, --C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂,--C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸ (R⁵)--C(O)R¹⁵, --C(O)O--R⁸--N(R⁵)R⁶, --C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)-P(O)(OR⁵)₂, or--C(N(R⁵)R⁶)=C(R¹⁸)R¹⁰, where:each R⁵ and R⁶ is independently hydrogenor alkyl; R⁸ is a straight or branched alkylene chain; each R¹⁵ isindependently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, --R⁸--O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,heterocyclyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶),or heterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶)whereR⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl,and each R⁸ is independently a straight or branched alkylene, alkylideneor alkylidyne chain; and R¹⁸ is hydrogen, alkyl aryl, aralkyl, cyano,--C(O)OR⁵, or --NO₂.
 19. The compound of claim 18 selected from thegroup consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N"-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N"-(2-carboxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N"-(2-(morpholin-4-yl)ethyl)thioureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(((4-hydroxypiperidin-1-yl)methyl)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N"-(2-hydroxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(N'-methylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-hydroxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N"-(2-(chloro)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N"-(2-(acetoxy)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N"-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N"-(2-(chloro)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(((2-hydroxyphenyl)carbonyl)oxy)ethyl)ureido)-methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-cyanoamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-((fluoromethylcarbonyl)amino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-((2-aminoethoxy)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-((methylthio)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--N'-((phenylthio)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-nitro-1-(methylamino)ethenyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(((2-dimethylphosphoramidoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.20. The compound of claim 13 wherein:R¹⁰ is hydrogen, alkyl, haloalkyl,or --R⁸ --OR⁵ ; R¹¹ is cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p)--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), whereR⁵ and R⁶ are each independentlyhydrogen, alkyl, aryl or aralkyl; each R⁸ is independently a straight orbranched alkylene, alkylidene or alkylidyne chain; and each R⁹ isindependently alkyl, aryl or aralkyl; each R¹⁵ is independently alkyl,cycloalkyl, haloalkyl, aryl, aralkyl, --R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵,--N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R --C(O)OR⁵, heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), or heterocyclylalkyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --R⁸--OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶) whereR⁵ and R⁶ areindependently each hydrogen, alkyl, aryl or aralkyl, and each R⁸ isindependently a straight or branched alkylene, alkylidene or alkylidynechain.
 21. The compound of claim 20 selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-(morpholin-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(4-hydroxycyclohexyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(pyridin-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(thiazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--N'-(thiazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(4-(oxo)oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(pyridin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(dihydro-4(H)-1,3-oxazin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--Nt-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(t-butyl)--N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(((thiazol-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-methoxyethyl)-N-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(oxazol-2-yl)amino)methyl)-3-chiorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N-(4-trifluoromethyl-5-(methoxycarbonyl)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--N'-(dihydro-4(H)-1,3-oxazin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N-methyl--Nt-(5-methyloxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(tetrazol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--N(tetrazol-5-yl)amino)methyl-3-chiorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--N'-(4-methyloxazolin-2-yl)amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(pyrazol-3-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2,2,2-trifluoroethyl)--N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(4-(ethoxycarbonyl)oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((Nt-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1,2,4-triazol4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N-(pyridin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N!-(2-amino-6-methylpyrimidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-((1,2,4-oxadiazol-3-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-(imidazol-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-y)-2-[((4-((N'-methyl--N'-(3,4,5,6-tetrahydropyridin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-chloropyrimidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'ethyl--N'-((imidazol-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(4-aminopyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamideN-(5-chloropyridin-2-yl)-2-[((4-((Nt-(4-aminopyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(4-(methylamino)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-((3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-((3-((methylthio)methyl)-1,2,4-oxadiazol-5-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(1,3,2-dioxaphospholan-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.22. The compound of claim 12 wherein:R¹⁰ and R¹¹ together with thenitrogen to which they are attached form a N-heterocyclic ringcontaining zero to three additional hetero atoms, where theN-heterocylic ring is optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, aryl,aralkyl, oxo, nitro, cyano, --R⁸ --CN, =N(R¹⁷), --OR⁵, --C(O)OR⁵, --R⁸--C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, --R⁸ --C(O)N(R⁵)R⁶,--N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to6), --S(O)p--R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0to 2), --(R⁸ --O),R⁵ (where t is 1 to 6), and heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), whereR⁵ and R⁶ are each independentlyhydrogen, alkyl, aryl or aralkyl; each R⁸ is independently a straight orbranched alkylene, alkylidene or alkylidyne chain; each R⁹ isindependently alkyl, aryl or aralkyl; each R¹⁷ is independentlyhydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵,--R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸ --C(O)--N(R⁵)R⁶ whereR⁵ and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and each R⁸ isindependently a straight or branched alkylene, alkylidene or alkylidynechain.
 23. The compound of claim 22 wherein the N-heterocylic ring isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, andnitro.
 24. The compound of claim 23 selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((4,5-dihydropyrazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((morpholin-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((pyrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((hydantoin-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((1,4,5,6-tetrahydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((pyrrolidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2,3,4,5,6,7-hexahydro-3,7-dimethyl-2,6-dioxo-1H-purin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;N-(pyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;N-(5-bromopyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((5-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2,4-dimethylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2,5-dimethylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-methyl-4-nitroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4,5-dichloroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(chloromethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((2-(fluoromethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.25. The compound of claim 22 wherein the N-heterocylic ring issubstituted by one or more substituents selected from the groupconsisting of alkyl, nitro, --R⁸ --CN, --OR⁵, --N(R⁵)--N(R⁵)R⁶,--C(O)R⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸ --O)_(t) R⁵ (wheret is 1 to 6), and heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶),whereR⁵ and R⁶ are each independently hydrogen, alkyl, aryl or aralkyl;each R⁸ is independently a straight or branched alkylene, alkylidene oralkylidyne chain; each R⁹ is independently alkyl, aryl or aralkyl. 26.The compound of claim 25 selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((4-(hydroxymethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((5-(hydroxymethyl)imidazol-1-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(methoxymethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(hydroxymethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-formylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(Namino--N'-methylamino)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-hydroxypiperidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylthio)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-(methylsulfonyl)piperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-methyl-4-nitroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(cyanomethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.27. The compound of claim 22 wherein the N-heterocylic ring issubstituted by one or more substituents selected from the groupconsisting of alkyl, oxo, --OR⁵ =N(R¹⁷), --C(O)OR⁵, --N(R⁵)R⁶,--C(O)N(R⁵)R⁶, --(R⁸ --O)_(t) R⁵, and heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), whereR⁵ and R⁶ are each independentlyhydrogen, alkyl, aryl or aralkyl; each R⁸ is independently a straight orbranched alkylene, alkylidene or alkylidyne chain; each R¹⁷ isindependently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵, --R⁸ --OR⁵,or --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, --R⁸ --C(O)--N(R⁵)R⁶whereR⁵ and R⁶ are independently each hydrogen, alkyl, aryl or aralkyl,and each R⁸ is independently a straight or branched alkylene, alkylideneor alkylidyne chain.
 28. The compound of claim 27 wherein theN-heterocylic ring is substituted by =N(R¹⁷) and is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, --C(O)N(R⁵)R⁶,and --(R⁸ --O)_(t) --R⁵, whereR⁵ and R⁶ are each independently hydrogen,alkyl, aryl or aralkyl; each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain; each R¹⁷ is independentlyhydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵,--R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸ --C(O)--N(R⁵)R⁶ whereR⁵ and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and each R⁸ isindependently a straight or branched alkylene, alkylidene or alkylidynechain.
 29. The compound of claim 28 selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5,5(dimethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-ethylimino-5,5-(dimethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5,5-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(S)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-imino tetrahydrooxazol -3-yl)methyl)-3-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((trans4,5-dimethyl-2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((cis4,5-dimethyl-2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((3-methyl-2-imino-2,3-dihydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-1,2-dihydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-(hydroxymethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrothiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-oxoimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((tetrahydro-2-imino-2H-pyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(methoxycarbonylamino)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(cyanoimino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-3-((phenylamino)carbonyl)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((cis4,5-dimethoxy-2-iminotetrahydroimidazol-l-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-amino4-imino-1,4-dihydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-((2-hydroxyethyl)imino)tetrahydroimidazol-l-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-iminopiperidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-imino-1(4H)-pyridinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-1(2M)-pyridin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylimino)pyrrolidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((2-(((aminocarbonyl)methyl)imino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.30. The compound of claim 22 wherein the N-heterocylic ring issubstituted by --N(R⁵)R⁶ and optionally substituted by one or moresubstituents selected from the group consisting of alkyl, oxo,--N(R⁵)R⁶, --OR⁵, and --C(O)N(R⁵)R⁶, where R⁵ and R⁶ are eachindependently hydrogen, alkyl, aryl or aralkyl.
 31. The compound ofclaim 30 selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((5-aminotetrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((3-amino-1,2,4-triazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((3,5-diamino-4H-1,2,4-triazol-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((4-amino-5-(aminocarbonyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2,6-diaminopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2,6-diaminopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((5-amino-2-oxo-2H-pyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((6-aminopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((6-aminopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-6-oxopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-6-oxopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((5-(dimethylamino)-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((5-amino-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2,4-diamino-6-hydroxypyrimidin-5-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-(1-methylethyl)aminolmidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((3-dimethylamino-5-methylpyrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((3-dimethylamino-5-methylpyrazol-2-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.32. The compound of claim 11 wherein:each R¹⁴ is independently alkyl,--R⁸ --CN, --C(R⁷)H--R⁸ --N(R¹⁰)R¹¹, --C(R⁷)H--R⁸ --N.sup.⊕ (R⁹)(R¹⁶)₂,--C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--O--R¹⁵, --C(R⁷)H--S(O)_(p)--R¹⁵ (where p is 0 to 2), --C(R⁷)H--N(R⁵)--(R⁵)_(t) --R⁵ (where t is 1to 6), --C(R⁷)H--N(R⁵)--R⁸ --[CH(OH)]_(t) CH₂ --OR⁵ (where t is 1 to 6),--C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹, --C(R⁷)H--O--N(R⁵)R⁶, orheterocyclyl (wherein the heterocyclyl radical is not attached to theradical of formula (i) through a nitrogen atom and is optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), where R⁵ and R⁶ are eachindependently hydrogen, alkyl, aryl or aralkyl; each R⁷ is independentlyhydrogen or alkyl; each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain; R¹⁰ and R¹¹ are eachindependently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano,--R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸--S(O)_(p) --R¹⁵ (where p is 0 to 2), --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁵--C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸ --C(O)NH₂, --C(S)NH₂,--C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸ --C(O)--N(R⁵)R¹⁵,--C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸ --N(R⁵)--C(O)R¹⁵,--C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)=C(R¹⁸)R¹⁰, --R⁸ --N(R⁵)-P(O)(OR⁵)₂,cycloalkyl (optionally substituted by one or more substituents selectedfrom the group consisting of alkyl, halo and --OR⁵), heterocyclyl(optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo,--OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹ (where pis 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶ and--C(O)N(R⁵)R⁶), whereR⁵ and R⁶ are each independently hydrogen, alkyl,aryl or aralkyl; each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain; each R⁹ is independentlyalkyl, aryl or aralkyl; each R¹⁵ is independently alkyl, cycloalkyl,haloalkyl, aryl, aralkyl, --R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --RN(R⁵)R⁶, --R⁸ --C(O)OR⁵, heterocyclyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), whereR⁵ and R⁶ are independently each hydrogen, alkyl,aryl or aralkyl, and each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain; or R⁵ and R¹⁵ together withthe nitrogen to which they are attached form a N-heterocyclic ringcontaining zero to three additional hetero atoms, where theN-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl, whereeach R⁵ ishydrogen, alkyl, aryl or aralkyl; and R¹⁸ is hydrogen, alkyl, aryl,aralkyl, cyano, --C(O)OR⁵, or --NO₂ ; or R¹⁰ and R¹¹ together with thenitrogen to which they are attached form a N-heterocyclic ringcontaining zero to three additional hetero atoms, where theN-heterocylic ring is optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, aryl,aralkyl, oxo, nitro, cyano, --R⁸ --CN, =N(R¹⁷), --OR⁵, --C(O)OR⁵, --R⁸--C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, --R⁸ --C(O)N(R⁵)R⁶,--N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where pis 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and heterocyclyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), whereR⁵ and R⁶ are eachindependently hydrogen, alkyl, aryl or aralkyl; each R⁸ is independentlya straight or branched alkylene, alkylidene or alkylidyne chain; each R⁹is independently alkyl, aryl or aralkyl; each R¹⁷ is independentlyhydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵,--R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸ --C(O)--N(R⁵)R⁶, whereR⁵ and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and each R⁸ isindependently a straight or branched alkylene, alkylidene or alkylidynechain; each R¹⁶ is independently alkyl, aryl, aralkyl, --R⁸ --OR⁵, --R⁸--N(R⁵)R⁶, cycloalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), whereR⁵ andR⁶ are independently each hydrogen, alkyl, aryl or aralkyl, and each R⁸is independently a straight or branched alkylene, alkylidene oralkylidyne chain; or both R16,s together with the nitrogen to which theyare attached (and wherein the R⁹ substituent is not present) form anaromatic N-heterocyclic ring containing zero to three additional heteroatoms, where the N-heterocylic ring is optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, --OR⁵, --R⁸ OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O),R⁵ (where t is 1 to 6), and --(R⁸--O)_(t) --R⁵ (where t is I to 6), whereR⁵ and R⁶ are independently eachhydrogen, alkyl, aryl or aralkyl, and each R⁸ is independently astraight or branched alkylene, alkylidene or alkylidyne chain.
 33. Thecompound of claim 32 selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((pyridinium-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide,N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(hydroxyethoxy)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((methylsulfinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(((2-hydroxyethyl)sulfinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((pyridinium-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-cyanomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(2-methylaminoethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(hydroxy)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(((imidazol-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((imidazolin-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(((5-hydroxymethyl-1-methylimidazol-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(((diethylamino)oxy)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-(imidazolin-2-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.34. The compound of claim 11 wherein:each R¹⁴ is independently--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹ --C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰, or--C(R⁷)H--C(NR¹⁷)--N(R⁵)R⁶, whereR⁵ and R⁶ are each independentlyhydrogen, alkyl, aryl or aralkyl; each R⁷ is independently hydrogen oralkyl; each R⁹ is independently alkyl, aryl or aralkyl; R¹⁰ and R¹ " areeach independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl,cyano, --R⁸ --CN, --OR⁵, --R⁸ --OR⁵, --S(O)p--R¹⁵ (where p is 0 to 2),--R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2), --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶,--R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --R⁸ --C(O)NH₂, --C(S)NH₂,--C(O)--S--R⁵, --C(O)--N(R⁵)R¹⁵, --R⁸ --C(O)--N(R⁵)R¹⁵,--C(S)--N(R⁵)R¹⁵, --R⁸ --N(R⁵)--C(O)H, --R⁸ --N(R⁵)--C(O)R¹⁵,--C(O)O--R⁸ --N(R⁵)R⁶, --C(N(R⁵)R⁶)=C(R¹⁸)R¹⁰, --R⁸ --N(R⁵)--P(O)(OR⁵)₂,cycloalkyl (optionally substituted by one or more substituents selectedfrom the group consisting of alkyl, halo and --OR⁵), heterocyclyl(optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo,--OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)p--R9 (where p is 0 to 2), --R⁸--S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --R⁸ --OR , --C(O)OR⁵, --S(O)_(p) --R⁹ (where pis 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶ and--C(O)N(R⁵)R⁶), whereR⁵ and R⁶ are each independently hydrogen, alkyl,aryl or aralkyl; each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain; each R⁹ is independentlyalkyl, aryl or aralkyl; each R¹⁵ is independently alkyl, cycloalkyl,haloalkyl, aryl, aralkyl, --R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶,--R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, heterocyclyl (optionally substituted byone or more substituents selected from the group consisting of alkyl,aryl, aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶,and --C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), whereR⁵ and R⁶ are independently each hydrogen, alkyl,aryl or aralkyl, and each R⁸ is independently a straight or branchedalkylene, alkylidene or alkylidyne chain; or R⁵ and R¹⁵ together withthe nitrogen to which they are attached form a N-heterocyclic ringcontaining zero to three additional hetero atoms, where theN-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,amino, monoalkylamino, dialkylamino, --OR⁵, --C(O)OR⁵, aminocarbonyl,monoalkylaminocarbonyl, and dialkylaminocarbonyl, whereeach R⁵ ishydrogen, alkyl, aryl or aralkyl; and R¹⁸ is hydrogen, alkyl, aryl,aralkyl, cyano, --C(O)OR⁵, or --NO₂ ; or R¹⁰ and R¹¹ together with thenitrogen to which they are attached form a N-heterocyclic ringcontaining zero to three additional hetero atoms, where theN-heterocylic ring is optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, aryl,aralkyl, oxo, nitro, cyano, --R⁸ --CN, =N(R¹⁷), --OR⁵, --C(O)OR⁵, --R⁸--C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, --R⁸ --C(O)N(R⁵)R⁶,--N(R⁵)--N(R⁵)R⁶, --C(O)R⁵, --C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to6), --S(O)_(p) --R⁹ (where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where pis 0 to 2), --(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and heterocyclyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶, and --C(O)N(R⁵)R⁶), where R⁵ and R⁶ are eachindependently hydrogen, alkyl, aryl or aralkyl; each R8 is independentlya straight or branched alkylene, alkylidene or alkylidyne chain; each R⁹is independently alkyl, aryl or aralkyl; each R¹⁷ is independentlyhydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵,--R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸ --C(O)--N(R⁵)R⁶, whereR⁵ and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and each R⁸ isindependently a straight or branched alkylene, alkylidene or alkylidynechain; each R¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano,--OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶, whereR⁵ and R⁶ are independently each hydrogen, alkyl,aryl or aralkyl, and each R8 is independently a straight or branchedalkylene, alkylidene or alkylidyne chain.
 35. The compound of claim 34selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-(((amidino)(methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-iminoethyl)--N'-methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(N',N"-dimethyl--N'"-cyanoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(N'-methyl-N"-hydroxyguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(N'-methyl-N"-(2-aminoethyl)-N'"-cyanoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(N'-methyl-N"-aminoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-(N',N"-dimethyl--N'"-(aminocarbonyl)guanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(imino(phenyl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(i-imino-2-(aminocarbonyl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-imino4,4,4-trifluorobutyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(imino(pyridin4-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(imino(thiophen-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(imino(pyrazin-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(cyclopropyl(imino)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--N'-(3-cyano-1-iminopropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(1-imino-4,4,4-trifluorobutyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-(2-amino-2-(hydroxylmino)ethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.36. The compound of claim 1 wherein:A is =N--; m is 1; n is 1; D is--N(H)--C(O)--; E is --C(O)--N(H)-- (where the nitrogen is bonded to the2-position of the pyridinyl ring); R² is --N(R¹⁰)R¹¹ where:R¹⁰ and R¹¹are each independently hydrogen, alkyl or --R⁸ --O--R⁵ where R⁸ is analkylene chain, and R⁵ is hydrogen or alkyl; or R¹⁰ and R¹¹ togetherwith the nitrogen to which they are attached form a N-heterocyclic ringcontaining zero to three additional hetero atoms, where theN-heterocylic ring is optionally substituted by one or more substituentsselected from the group consisting of alkyl and --C(O)OR⁵ where R⁵ ishydrogen or alkyl; R³ is a radical of the formula (i): ##STR63## where ris 1; R¹³ is halo; andR¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ or --C(R⁷)H--N(R⁵)--R⁸--[CH(OH)]_(t) --CH₂ --OR⁵ (where t is 1 to 3)where: each R⁵ isindependently hydrogen or alkyl; R⁷ is hydrogen; R⁸ is a straight orbranched alkylene chain; R¹⁰ and R¹¹ are each independently hydrogen,alkyl, formyl, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸--N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂,--C(O)--N(R⁵)R¹¹, --C(S)--N(R⁵)R¹⁵, cycloalkyl (optionally substitutedby --OR⁵), heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, haloalkyl,oxo, --OR⁵, and --C(O)OR⁵), or heterocyclylalkyl (optionally substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, oxo, --OR⁵, and --C(O)OR⁵), where:each R⁵ and R⁶ isindependently hydrogen or alkyl; each R⁸ is independently a straight orbranched alkylene chain; and each R¹⁵ is alkyl, --R⁸ --OR⁵, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by --R⁸ --OR⁵), orheterocyclylalkyl (optionally substituted by --OR⁵); or R¹⁰ and R¹⁰together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, oxo, =N(R¹⁷),--OR⁵, --R⁸ --OR⁵, and --N(R⁵)R⁶ ; whereeach R⁵ and R⁶ is independentlyhydrogen or alkyl; R⁸ is a straight or branched alkylene chain; and eachR¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵, --R⁸--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶ ; and R⁴ is in the 5-position and is hydrogen or halo.37. The compound of claim 36 wherein:R² is --N(R¹⁰)R¹¹ where:R¹⁰ and R¹¹are each independently hydrogen, alkyl or --R⁸ --O--R⁵ where R⁸ is analkylene chain, and R⁵ is hydrogen or alkyl.
 38. The compound of claim37 wherein:R¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where:R⁷ is hydrogen; R¹⁰ and R¹¹are each independently hydrogen, alkyl, formyl, --R⁸ --OR⁵, --S(O)_(p)--R¹⁵ (where p is 0 to 2), --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵,--C(O)NH₂, --C(S)NH₂, --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, cycloalkyl(optionally substituted by --OR⁵), heterocyclyl (optionally substitutedby one or more substituents selected from the group consisting of alky,haloalkyl, oxo, --OR⁵, and --C(O)OR⁵), or heterocyclylalkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, haloalkyl, oxo, --OR⁵, and --C(O)OR⁵); where:eachR⁵ and R⁶ is independently hydrogen or alkyl; each R⁸ is independently astraight or branched alkylene chain; and each R¹⁵ is alkyl, --R⁸ --OR⁵,--R⁸ --C(O)OR⁵, heterocyclyl (optionally substituted by --R⁸ --OR⁵), orheterocyclylalkyl (optionally substituted by --OR⁵); or R¹⁰ and R¹¹together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, oxo, =N(R¹⁷),--OR⁵, --R⁸ --OR⁵, and --N(R⁵)R⁶ ; where:each R⁵ and R⁶ is independentlyhydrogen or alkyl; R⁸ is straight or branched alkylene chain; and eachR¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵, --R⁸OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶.
 39. The compound of claim 38 selected from the groupconsistingof:N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(1-methylpiperidin4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;and N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(di(2-methoxyethyl)amino)-5-chlorobenzamide.40. The compound of claim 36 whereinR² is --N(R¹⁰)R¹¹ where:R¹⁰ and R¹¹together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl and --C(O)OR⁵where R⁵ is hydrogen or alkyl.
 41. The compound of claim 40 selectedfrom the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(morpholin-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropynidin-2-yl)-2-[((4-((N'-methyl--N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-methoxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methylsulfonyl--N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolidin-1-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-(1-methylethyl)--N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(ethoxycarbonyl)piperidin-1-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--Nt-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(carboxy)piperidin-1-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--Nt-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-ethylpiperazin-1-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--Nt-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((Nt-methyl--Nt-(4-trifluoromethyl-5-(methoxycarbonyl)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(4-trifluoromethyl-5-carboxypyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin4-yl)-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(tetrazol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin4-yl)-5-chlorobenzamide.42. The compound of claim 1 wherein:A is =N--; m is 1; n is 1; D is--N(H)--C(O)--; E is --C(O)--N(H)-- (where the nitrogen is bonded to the2-position of the pyridinyl ring); R² is --O--(R⁸ --O)_(t) R⁵ (where tis 1 to 3) or --O--(R⁸ --O)_(t) --R¹⁹ where R⁵ is hydrogen or alkyl,each R⁸ is independently a straight or branched alkylene chain, and R¹⁹is heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo,or haloalkyl); R³ is a radical of the formula (i): ##STR64## where r is1; R¹³ is halo; andR¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ or --C(R⁷)H--N(R⁵)--R⁸--[CH(OH)], --CH₂ --OR⁵ (where t is 1 to 6) where:each R⁵ isindependently hydrogen or alkyl; R⁸ is a straight or branched alkylenechain; R⁷ is hydrogen; R¹⁰ and R¹¹ are each independently hydrogen,alkyl, formyl, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R--N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂,--C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, cycloalkyl (optionally substitutedby --OR⁵), heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, haloalkyl,oxo, --OR⁵, and --C(O)OR⁵), or heterocyclylalkyl (optionally substitutedby one or more substituents selected from the group consisting of alkyl,haloalkyl, oxo, --OR⁵, and --C(O)OR⁵); where:each R⁵ and R⁶ isindependently hydrogen or alkyl; each R⁸ is independently a straight orbranched alkylene chain; and each R¹⁵ is alkyl, --R⁸ --OR⁵, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by --R⁸ --OR⁵), orheterocyclylalkyl (optionally substituted by --OR⁵); or R¹⁰ and R¹¹together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, oxo, =N(R¹⁷),--OR⁵, --R⁸ --OR⁵, and --N(R⁵)R⁶ ; whereeach R⁵ and R⁶ is independentlyhydrogen or alkyl; R⁸ is straight or branched alkylene chain; and eachR¹⁷ is independently hydrogen, alkyl, aryl, aralkyl, cyano, --OR⁵, --R⁸--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --C(O)--N(R⁵)R⁶, or --R⁸--C(O)--N(R⁵)R⁶ ; and R⁴ is in the 5-position and is hydrogen or halo.43. The compound of claim 42 selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-ethyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--Nt-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyridin-3-yloxy)propoxy)-5-chlorobenzamide.44. The compound of claim 1 wherein:A is =N--; m is 1; n is 1; D is--N(H)--C(O)--; E is --C(O)--N(H)-- (where the nitrogen is bonded to the2-position of the pyridinyl ring); R² is --O--R --N(R¹⁰)R¹¹ where:R⁸ isa straight or branched alkylene chain; and R¹⁰ and R¹¹ are eachindependently hydrogen, alkyl or --R⁸ --O--R⁵ where R⁸ is an alkylenechain, and R⁵ is hydrogen or alkyl; or R¹⁰ and R¹¹ together with thenitrogen to which they are attached form a N-heterocyclic ringcontaining zero to three additional hetero atoms, where theN-heterocylic ring is optionally substituted by one or more substituentsselected from the group consisting of alkyl and --C(O)OR⁵ where R⁵ ishydrogen or alkyl; R³ is a radical of the formula (i): ##STR65## where ris 1; R¹³ is halo; andR¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where:R⁷ is hydrogen;R¹⁰ and R¹¹ are each independently hydrogen, alkyl, formyl, --R⁸ --OR⁵,--S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,--C(O)--R₁₅, --C(O)NH₂, --C(S)NH₂, --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵,cycloalkyl (optionally substituted by --OR⁵), heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, haloalkyl, oxo, --OR⁵, and --C(O)OR⁵), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, haloalkyl, oxo, --OR⁵ and--C(O)OR⁵), where:each R⁵ and R⁶ is independently hydrogen or alkyl;each R⁸ is independently a straight or branched alkylene chain; and eachR¹⁵ is alkyl, --R⁸ --OR⁵, --R⁸ --C(O)OR⁵, heterocyclyl (optionallysubstituted by --R⁸ --OR⁵), or heterocyclylalkyl (optionally substitutedby --OR⁵); and R⁴ is in the 5-position and is hydrogen or halo.
 45. Thecompound of claim 44 selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(imidazol-1-yl)ethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(imidazol-I-yl)propoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(pyrrolidin-1-yl)ethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(imidazol-I-yl)ethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(pyrrolidin-1-yl)ethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--Nt-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(4-ethylpiperazin-1-yl)propoxy)-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-aminoethoxy)-5-chlorobenzamide.46. The compound of claim 1 wherein:A is =N--; m is 1; n is 1; D is--N(H)--C(O)--; E is --C(O)--N(H)-- (where the nitrogen is bonded to the2-position of the pyridinyl ring); R² is --O--R⁸ --O--C(O)R⁵, --O--R⁸--CH(OH)--CH₂ --N(R¹⁰)R¹¹, or --O--R⁸ --CH(OH)--CH₂ --OR⁵ whereeach R⁵is hydrogen or alkyl; R⁸ is a straight or branched alkylene chain; andR¹⁰ and R¹¹ are each independently hydrogen, alkyl or --R⁸ --O--R⁵ whereR⁸ is an alkylene chain, and R⁵ is hydrogen or alkyl; or R¹⁰ and R¹¹together with the nitrogen to which they are attached form aN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocylic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl and --C(O)OR⁵where R⁵ is hydrogen or alkyl; R³ is a radical of the formula (i):##STR66## where r is 1; R¹³ is halo; andR¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ or--C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹ where:R⁵ is hydrogen or alkyl; R⁷ ishydrogen; R¹⁰ and R¹¹ are each independently hydrogen, alkyl, formyl,--R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, --C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂, --C(O)--N(R⁵)R¹⁵,--C(S)--N(R⁵)R¹⁵, cycloalkyl (optionally substituted by --OR⁵),heterocyclyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, haloalkyl, oxo, --OR⁵, and--C(O)OR⁵), or heterocyclylalkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, haloalkyl,oxo, --OR⁵, and --C(O)OR⁵); where:each R⁵ and R⁶ is independentlyhydrogen or alkyl; each R⁸ is independently a straight or branchedalkylene chain; and each R is alkyl, --R⁸ --OR⁵, --R⁸ --C(O)OR⁵,heterocyclyl (optionally substituted by --R⁸ --OR⁵), orheterocyclylalkyl (optionally substituted by --OR⁵); and R⁴ is in the5-position and is hydrogen or halo.
 47. The compound of claim 46selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-acetoxyethoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(imidazol-1-yl)propoxy)-5-chlorobenzamide;andN-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-methoxypropoxy)-5-chlorobenzamide.48. The compound of claim 1 wherein:A is =N--; m is 1 to 3; n is 1; D is--N(R⁵)--C()--(where Z is oxygen and R⁵ is hydrogen or alkyl); E is--C(Z)--N(R⁵)--(where Z is oxygen, R⁵ is hydrogen or alkyl, and thenitrogen is attached to the pyridinyl ring); each R¹ is independentlyhydrogen, halo or --OR⁵ ; or two adjacent R^(1') s together with thecarbons to which they are attached form a dioxole ring fused to thephenyl ring wherein the dioxole ring is optionally substituted by alkyl;R² is hydrogen; R³ is a radical of the formula (i): ##STR67## where r is1; R¹³ is halo; andR¹⁴ is --C(R⁷)H--N(R¹⁰)R¹¹ where:R⁷ is hydrogen; andR¹⁰ and R¹¹ are each independently hydrogen, alkyl, formyl, --R⁸ --OR⁵,--S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,--C(O)--R¹⁵, --C(O)NH₂, --C(S)NH₂, --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵,cycloalkyl (optionally substituted by --OR⁵), heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, haloalkyl, oxo, --OR⁵, and --C(O)OR⁵), orheterocyclyalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, haloalkyl, oxo, --OR⁵, and--C(O)OR⁵); where:each R⁵ and R⁶ is independently hydrogen or alkyl;each R⁸ is independently a straight or branched alkylene chain; and eachR¹⁵ is alkyl, --R⁸ --OR⁵, --R⁸ --C(O)OR⁵, heterocyclyl (optionallysubstituted by --R⁸ --OR⁵), or heterocyclyalkyl (optionally substitutedby --OR⁵); and R⁴ is in the 5-position and is hydrogen or halo.
 49. Thecompound of claim 48 selected from the group consistingof:N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3,4,5-trimethoxybenzamide;5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N'-methyl--N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole;5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N'-methyl--N'-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole;and5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N'-(2-methoxyethyl)--N'-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole.50. A method of treating a human having a disease-state characterized bythrombotic activity, wherein the method comprises administering to ahuman in need thereof a therapeutically effective amount of a compoundof formula (I): ##STR68## wherein: A is =N--;m is 1 to 3; n is 1 to 4; Dis --N(R⁵)--C(Z)-- or --N(R⁵)--S(O)_(p) -- (where p is 0 to 2; Z isoxygen, sulfur or H₂ ; and the nitrogen atom is directly bonded to thephenyl ring having the R¹ and R² substituents); E is --C(Z)--N(R⁵)-- or--S(O)_(p) --N(R⁵)--(where p is 0 to 2; Z is oxygen, sulfur or H₂ ; andthe nitrogen atom can be bonded to the phenyl ring having the R¹ and theR² substituents or to the aromatic ring having the R⁴ substituent); eachR¹ is independently hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl,cyano, --OR⁵, --S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵,--C(O)N(R⁵)R⁶, --N(R⁵)R⁶, --O--C(O)R⁵, or --N(R⁵)--CH(R¹²)--C(O)OR⁵ ; ortwo adjacent R¹, s together with the carbons to which they are attachedform a heterocyclic ring fused to the phenyl ring wherein theheterocyclic ring is optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl and aralkyl; R² ishydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, --OR⁵,--S(O)_(p) --R⁹ (where p is 0 to 2), --C(O)OR⁵, --OC(O)--R⁵,--C(O)N(R⁵)R⁶, --N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸--N(R¹⁰)R¹¹, --C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--S(O)_(p) --R⁹(where p is 0 to 2), --C(R⁷)H--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2),--O--R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --C(R⁷)H--N(R⁵)R⁶,--C(R⁷)H--R⁸ --N(R⁵)R⁶, --O--R⁸ --CH(OH)--CH₂ --N(R¹⁰)R¹¹, --O--R⁸--N(R¹⁰)R¹¹, --O--R⁸ --O--C(O)R⁵, --O--R⁸ --CH(OH)--CH₂ --OR⁵, --O--(R⁸--O)_(t) --R⁵ (where t is 1 to 6), --O--(R⁸ --O)_(t) --R¹⁹ (where t is 1to 6), --O--R⁸ --C(O)R⁵, --O--R⁸ --C(O)R¹⁹, --O--R⁸ --C(O)OR⁵,--N(R⁵)--R⁸ --N(R¹⁰)R¹¹, --S(O)_(p) --R⁸ --N(R⁵)R⁶ (where p is 0 to 2),--S(O)_(p) --R⁸ --C(O)OR⁵ (where p is 0 to 2), or--N(R⁵)--CH(R¹²)--C(O)OR⁵ ; R³ is a radical of formula (i): ##STR69##where: r is 1 or 2;R¹³ is hydrogen, alkyl, halo, haloalkyl, --N(R⁵)R⁶,--C(R⁷)H--N(R⁵)R⁶, OR⁵, --R^(8--OR) ⁵, --S(O)_(p) --R⁸ --N(R⁵)R⁶ (wherep is 0 to 2) or heterocyclylalkyl (where the heterocyclic ring isoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, aralkyl, nitro and cyano); and each R¹⁴is independently hydrogen, alkyl, halo, formyl, acetyl, cyano, --R⁸--CN, --N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)R¹¹, --C(R⁷)H--R⁸ --N(R¹⁰)R¹¹,--C(R⁷)H--N.sup.⊕ (R⁹)(R¹⁶)₂, --C(R⁷)H--R⁸ --N.sup.⊕ (R⁹)(R¹⁶)₂,--C(O)OR⁵, --C(R⁷)H--C(O)OR⁵, --C(R⁷)H--R⁸ --C(O)OR⁵, --OR⁵,--C(R⁷)H--OR⁵, --C(R⁷)H--R⁸ --OR⁵, --C(R⁷)H--O--R¹⁵, --S(O)_(p) --R¹⁵(where p is 0 to 2), --C(R⁷)H--S(O)_(p) --R¹⁵ (where p is 0 to 2),--C(R⁷)H--R⁸ --S(O)_(p) --R¹⁵ (where p is 0 to 2), --S(O)_(p) --N(R⁵)R⁶(where p is 0 to 2), --C(O)N(R⁵)R⁶, --C(R⁷)H--C(O)N(R⁵)R⁶, --C(R⁷)H--R⁸--C(O)N(R⁵)R⁶, --C(R⁷)H--N(R⁵)--(R⁸ --O)t--R⁵ (where t is 1 to 6),--C(R⁷)H--R⁸ --N(R⁵)--(R⁸ -O)_(t) --R⁵ (where t is 1 to 6),--C(R⁷)H--O--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --C(R⁷)H--R --O--(R⁸--O)_(t) --R⁵ (where t is 1 to 6), --O--R⁸ --CH(OH)--CH₂ --OR⁵,--C(R⁷)H--O--R⁸ --CH(OH)--CH₂ --OR⁵, --C(R⁷)H--N(R⁵)--R⁸ -[CH(OH)]_(t)--CH₂ --OR⁵ (where t is 1 to 6), --C(R⁷)H--N(R⁵)--S(O)₂ --N(R¹⁰)R¹¹,--C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--N(R¹⁰)R¹¹, --C(R⁷)H--N(R¹⁰)--C(NR¹⁷)--R¹⁰,--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--C(NR¹⁷)--N(R⁵)R⁶, --C(R⁷)H--O--N(R⁵)R⁶,heterocyclyl (wherein the heterocyclyl radical is not attached to theradical of formula (i) through a nitrogen atom and is optionallysubstituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), or heterocyclylalkyl (whereinthe heterocyclyl radical is not attached to the alkyl radical through anitrogen atom and is optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); each R⁴is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, --OR⁵,--C(O)OR⁵, --N(R⁵)R⁶, --C(O)N(R⁵)R⁶, or --R⁸ --N(R⁵)R⁶ ; R⁵ and R⁶ areeach independently hydrogen, alkyl, aryl or aralkyl; each R⁷ isindependently hydrogen or alkyl; each R⁸ is independently a straight orbranched alkylene, alkylidene or alkylidyne chain; each R⁹ isindependently alkyl, aryl or aralkyl; R¹⁰ and R¹¹ are each independentlyhydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, --R⁸ --CN,--OR⁵, --R⁸ --OR⁵, --S(O)_(p) --R¹⁵ (where p is 0 to 2), --R⁸ --S(O)_(p)--R¹⁵ (where p is 0 to 2), --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵,--C(O)--R¹⁵, --C(O)NH₂, --R⁸ --C(O)NH₂, --C(S)NH₂, --C(O)--S--R⁵,--C(O)--N(R⁵)R¹⁵, --R⁸ --C(O)--N(R⁵)R¹⁵, --C(S)--N(R⁵)R¹⁵, --R⁸--N(R⁵)--C(O)H, --R⁸ --N(R⁵)--C(O)R¹⁵, --C(O)O--R⁸ --N(R⁵)R⁶,--C(N(R⁵)R⁶)=C(R¹⁸)R¹⁰, --R⁸ --N(R⁵)-P(O)(OR⁵)₂, cycloalkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo and --OR⁵), heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, --OR⁵, --R⁸--OR⁵, --C(O)OR⁵, --S(O)_(p) --R9 (where p is 0 to 2), --R --S(O)_(p)--R⁹ (where p is 0 to 2), --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, oxo, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --S(O)_(p) --R⁹ (where pis 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --N(R⁵)R⁶ and--C(O)N(R⁵)R⁶); or R¹⁰ and R¹¹ together with the nitrogen to which theyare attached form a N-heterocyclic ring containing zero to threeadditional hetero atoms, where the N-heterocyclic ring is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano,--R⁸ --CN, =N(R¹⁷), --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸--N(R⁵)R⁶, --C(O)N(R⁵)R⁶, --R⁸ --C(O)N(R⁵)R⁶, --N(R⁵)--N(R⁵)R⁶,--C(O)R⁵, --C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), --S(O)p--R9(where p is 0 to 2), --R⁸ --S(O)_(p) --R⁹ (where p is 0 to 2), --(R⁸-O)_(t) --R⁵ (where t is I to 6), and heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵,--N(R⁵)R⁶, and --C(O)N(R⁵)R⁶); R¹² is a side chain of an α-amino acid;each R¹⁵ is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl,--R⁸ --O--C(O)--R⁵, --R⁸ --OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --R⁸--C(O)OR⁵, heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶, and--C(O)N(R⁵)R⁶); or R⁵ and R¹⁵ together with the nitrogen to which theyare attached form a N-heterocyclic ring containing zero to threeadditional hetero atoms, where the N-heterocyclic ring is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino,--OR⁵, --C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, anddialkylaminocarbonyl; each R¹⁶ is independently alkyl, aryl, aralkyl,--R⁸ --OR⁵, --R⁸ --N(R⁵)R⁶, cycloalkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, halo and--OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl,halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶), orheterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); or bothR^(16') s together with the nitrogen to which they are attached (andwherein the R⁹ substituent is not present) form an aromaticN-heterocyclic ring containing zero to three additional hetero atoms,where the N-heterocyclic ring is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, aralkyl,--OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵, --N(R⁵)R⁶, --R⁸ --N(R⁵)R⁶, --C(O)R⁵,--C(O)--(R⁸ --O)_(t) --R⁵ (where t is 1 to 6), and --(R⁸ --O)_(t) --R⁵(where t is 1 to 6); each R¹⁷ is independently hydrogen, alkyl, aryl,aralkyl, cyano, --OR⁵, --R⁸ --OR⁵, --C(O)OR⁵, --R⁸ --C(O)OR⁵,--C(O)--N(R⁵)R⁶, or --R⁸ --C(O)--N(R⁵)R⁶ ; R¹⁸ is hydrogen, alkyl, aryl,aralkyl, cyano, --C(O)OR⁶, or --NO₂ ; and each R¹⁹ is cycloalkyl,haloalkyl, --R⁸ --OR⁵, --R⁸ --N(R⁵)R⁶, --R⁸ --C(O)OR⁵, --R⁸--C(O)N(R⁵)R⁶, heterocyclyl (optionally substituted by alkyl, aryl,aralkyl, halo, haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ or --C(O)N(R⁵)R⁶),or heterocyclylalkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, aryl, aralkyl, halo,haloalkyl, --OR⁵, --C(O)OR⁵, --N(R⁵)R⁶ and --C(O)N(R⁵)R⁶); as a singlestereoisomer or a mixture thereof; or a pharmaceutically acceptable saltthereof.